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Abstract:

An organ perfusion apparatus and method monitor, sustain and/or restore
viability of organs and preserve organs for storage and/or transport.
Other apparatus include an organ transporter, an organ cassette and an
organ diagnostic device. The method includes perfusing the organ at
hypothermic and/or normothermic temperatures, preferably after
hypothermic organ flushing for organ transport and/or storage. The method
can be practiced with prior or subsequent static or perfusion hypothermic
exposure of the organ. Organ viability is restored by restoring high
energy nucleotide (e.g., ATP) levels by perfusing the organ with a
medical fluid, such as an oxygenated cross-linked hemoglobin-based
bicarbonate medical fluid, at normothermic temperatures. In perfusion,
organ perfusion pressure is preferably controlled in response to a sensor
disposed in an end of tubing placed in the organ, by a pneumatically
pressurized medical fluid reservoir, providing perfusion pressure fine
tuning, overpressurization prevention and emergency flow cut-off. In the
hypothermic mode, the organ is perfused with a medical fluid, preferably
a simple crystalloid solution containing antioxidants, intermittently or
in slow continuous flow. The medical fluid may be fed into the organ from
an intermediary tank having a low pressure head to avoid organ
overpressurization. Preventing overpressurization prevents or reduces
damage to vascular endothelial lining and to organ tissue in general.
Viability of the organ may be automatically monitored, preferably by
monitoring characteristics of the medical fluid perfusate. The perfusion
process can be automatically controlled using a control program.

Claims:

2. The organ transporting device according to claim 1, wherein the data
logger and/or transmitter is a global positioning system.

3. The organ transporting device according to claim 2, wherein the global
positioning system allows tracking of the location of the organ
transporting device.

4. The organ transporting device according to claim 1, wherein the data
logger and/or transmitter allows monitoring of an organ in the organ
transporting device at a location of the apparatus.

5. The organ transporting device according to claim 1, wherein the data
logger and/or transmitter allows monitoring of an organ in the organ
transporting device at a location other than a location of the apparatus.

6. The organ transporting device according to claim 1, wherein conditions
experienced by the system are detected and monitored.

7. The organ transporting device according to claim 1, wherein conditions
experienced by an organ are detected and or monitored.

8. The organ transporting device according to claim 1, wherein conditions
experienced by a perfusate are detected and monitored.

9. The organ transporting device according to claim 6, wherein the
conditions are compared with pre-stored operating conditions.

10. The organ transporting device according to claim 9, wherein a signal
is generated based on the comparison, the signal being indicative of
viability of an organ.

11. The organ transporting device according to claim 1, wherein the data
logger and/or transmitter logs and/or transmits data from at least one of
a pressure sensor, a pH detector, an oxygen sensor, and a flow meter.

12. The organ transporting device according to claim 1, wherein the data
logger and/or transmitter logs and/or transmits data from a pressure
sensor, a pH detector, an oxygen sensor, and a flow meter.

Description:

[0001] This is a Division of application Ser. No. 12/926,277 filed Nov. 5,
2010, which is a Continuation of application Ser. No. 12/662,930 filed
May 12, 2010, which is a Division of application Ser. No. 10/617,130
filed Jul. 11, 2003, now U.S. Pat. No. 7,824,848, which in turn is a
Division of application Ser. No. 09/645,525 filed Aug. 25, 2000, now U.S.
Pat. No. 6,673,594, which is a Continuation-in-part of application Ser.
No. 09/537,180 filed Mar. 29, 2000, now U.S. Pat. No. 6,977,140, and a
Continuation-in-part of application Ser. No. 09/162,128 filed Sep. 29,
1998, now abandoned. The disclosure of the prior applications is hereby
incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of Invention

[0003] The invention relates to an apparatus and method for perfusing one
or more organs to monitor, sustain and/or restore the viability of the
organ(s) and/or for transporting and/or storing the organ(s).

[0004] 2. Description of Related Art

[0005] Preservation of organs by machine perfusion has been accomplished
at hypothermic temperatures with or without computer control with
crystalloid perfusates and without oxygenation. See, for example, U.S.
Pat. Nos. 5,149,321, 5,395,314, 5,584,804, 5,709,654 and 5,752,929 and
U.S. patent application Ser. No. 08/484,601 to Klatz et al., which are
hereby incorporated by reference. Hypothermic temperatures provide a
decrease in organ metabolism, lower the energy requirements, delay the
depletion of high energy phosphate reserves and accumulation of lactic
acid and retard the morphological and functional deterioration associated
with disruption of blood supply. Oxygen can not be utilized efficiently
by mitochondria below approximately 20° C. to produce energy, and
the reduction in catalase/superoxide dismutase production and ascorbyl
and glutathione regeneration at low temperatures allows high free radical
formation. The removal of oxygen from perfusates during low temperature
machine perfusion has proven helpful in improving organ transplant
results by some investigators.

[0006] Reduction in potential oxygen damage is also accomplished via the
addition of antioxidants to the perfusate. In particular, this has proven
useful in reducing organ damage after long warm ischemia times. Numerous
other perfusate additives have also been reported to improve the outcome
of machine perfusion.

[0007] Ideally organs would be procured in a manner that limits their warm
ischemia time to essentially zero. Unfortunately, in reality, many
organs, especially from non-beating heart donors, are procured after
extended warm ischemia time periods (i.e., 45 minutes or more). The
machine perfusion of these organs at low temperature has demonstrated
significant improvement (Transpl Int 1996 Daemen). Further, prior art
teaches that the low temperature machine perfusion of organs is preferred
at low pressures (Transpl. Int 1996 Yland) with roller or diaphragm pumps
delivering the perfusate at a controlled pressure. Numerous control
circuits and pumping configurations have been utilized to achieve this
objective and to machine perfuse organs in general. See, for example,
U.S. Pat. Nos. 5,338,662 and 5,494,822 to Sadri; U.S. Pat. No. 4,745,759
to Bauer et al.; U.S. Pat. Nos. 5,217,860 and 5,472,876 to Fahy et al.;
U.S. Pat. No. 5,051,352 to Martindale et al.; U.S. Pat. No. 3,995,444 to
Clark et al.; U.S. Pat. No. 4,629,686 to Gruenberg; U.S. Pat. Nos.
3,738,914 and 3,892,628 to Thorne et al.; U.S. Pat. Nos. 5,285,657 and
5,476,763 to Bacchi et al.; U.S. Pat. No. 5,157,930 to McGhee et al.; and
U.S. Pat. No. 5,141,847 to Sugimachi et al. However, in some situations
the use of such pumps for machine perfusion of organs may increase the
risk of overpressurization of the organ should the organ perfusion
apparatus malfunction. High pressure perfusion (e.g., above about 60 mm
Hg) can wash off the vascular endothelial lining of the organ and in
general damages organ tissue, in particular at hypothermic temperatures
where the organ does not have the neurological or endocrinal connections
to protect itself by dilating its vasculature under high pressure.

[0008] Furthermore, the techniques used for assessment of the viability of
these machine perfused organs have been a critical factor in limiting the
organs from greater use. While increased organ resistance (i.e.,
pressure/flow) measurements during machine perfusion are a useful
indicator, they demonstrate only the worst case situations.

[0009] During low temperature machine perfusion of organs that have been
damaged by warm ischemia time or by the machine perfusion itself, the
organs will elute intracellular and endothelial as well as membrane
constituents. Over the years the appearance of various ubiquitous
intracellular enzymes, such as lactic dehydrogenase (LDH) and alkaline
phosphatase, in the perfusate has been used as a biomarker of organ
damage. Recently, the determination of the presence of alpha
glutathione-S-transferase (a-GST) and Pi glutathione-S-transferase
(p-GST) in low temperature machine perfusion perfusates has proven a
satisfactory indicator in predicting the functional outcome of
non-beating heart donor kidney grafts before transplantation (Transpl
1997 Daemen).

[0010] The prior art has also addressed the need to restore or maintain an
organ's physiological function after preservation for an extended period
of time at hypothermic temperatures. In particular, U.S. Pat. No.
5,066,578 to Wikman-Coffelt discloses an organ preservation solution that
contains large amounts of pyruvate. Wikman-Coffelt teaches that flooding
of the organ with pyruvate bypasses glycosis, the step in the cell energy
cycle that utilizes adenosine triphosphate (ATP) to produce pyruvate, and
pyruvate is then available to the mitochondria for oxidative
phosphorylation producing ATP. Wikman-Coffelt teaches perfusing or
washing an organ at a warm temperature with a first preservation solution
containing pyruvate for removal of blood or other debris from the organ's
vessels and to vasodilate, increase flow and load the cells with an
energy supply in the form of a clean substrate, namely the pyruvate.
Wikman-Coffelt teaches that the pyruvate prevents edema, ischemia,
calcium overload and acidosis as well as helps preserve the action
potential across the cell membrane. The organ is then perfused with a
second perfusion solution containing pyruvate and a small percentage of
ethanol in order to stop the organ from working, vasodilate the blood
vessels allowing for full vascular flow, continue to load the cells with
pyruvate and preserve the energy state of the organ. Finally the organ is
stored in a large volume of the first solution for 24 hours or longer at
temperatures between 4° C. and 10° C.

[0011] However, the mitochondria are the source of energy in cells and
need significant amounts of oxygen to function. Organs naturally have
significant pyruvate levels, and providing an organ with additional
pyruvate will not assist in restoring and/or maintaining an organ's full
physiological function if the mitochondria are not provided with
sufficient oxygen to function. Further, briefly flooding an organ with
pyruvate may, in fact, facilitate tearing off of the vascular endothelial
lining of the organ.

[0012] U.S. Pat. No. 5,599,659 to Brasile et al. also discloses a
preservation solution for warm preservation of tissues, explants, organs
and endothelial cells. Brasile et al. teaches disadvantages of cold organ
storage, and proposes warm preservation technology as an alternative.
Brasile et al. teaches that the solution has an enhanced ability to serve
as a medium for the culture of vascular endothelium of tissue, and as a
solution for organs for transplantation using a warm preservation
technology because it is supplemented with serum albumin as a source of
protein and colloid; trace elements to potentiate viability and cellular
function; pyruvate and adenosine for oxidative phosphorylation support;
transferrin as an attachment factor; insulin and sugars for metabolic
support and glutathione to scavenge toxic free radicals as well as a
source of impermeant; cyclodextrin as a source of impermeant, scavenger,
and potentiator of cell attachment and growth factors; a high Mg++
concentration for microvessel metabolism support; mucopolysaccharides,
comprising primarily chondroitin sulfates and heparin sulfates, for
growth factor potentiation and hemostasis; and ENDO GRO® as a source
of cooloid, impermeant and specific vascular growth promoters. Brasile et
al. further teaches warm perfusing an organ for up to 12 hours at
30° C., or merely storing the organ at temperatures of 25°
C. in the preservation solution.

[0013] However, flooding an organ with such chemicals is insufficient to
arrest or repair ischemic injury where the mitochondria are not provided
with sufficient oxygen to function to produce energy. The oxygen needs of
an organ at more than 20° C. are substantial and cannot be met by
a simple crystalloid at reasonable flows. Further, assessment of the
viability of an organ is necessary before the use of any type of solution
can be determined to have been fruitful.

[0014] WO 88/05261 to Owen discloses an organ perfusion system including
an organ chamber that is supplied with an emulsion fluid or physiological
electrolyte that is transported through a perfusion system. The chamber
contains a synthetic sac to hold the organ. Perfusate enters the organ
through a catheter inserted into an artery. The perfusate is provided by
two independent fluid sources, each of which includes two reservoirs.

SUMMARY OF THE INVENTION

[0015] The present invention focuses on avoiding damage to an organ during
perfusion while monitoring, sustaining and/or restoring the viability of
the organ and preserving the organ for storage and/or transport. The
invention is directed to an apparatus and method for perfusing an organ
to monitor, sustain and/or restore the viability of the organ and/or for
transporting and/or storing the organ. More particularly, the organ
perfusion apparatus and method according to the invention monitor,
sustain and/or restore organ viability by perfusing the organ at
hypothermic temperature (hypothermic perfusion mode) and/or normothermic
temperatures (normothermic perfusion mode) preferably after flushing of
the organ such as by hypothermic flushing followed by static organ
storage and/or organ perfusion at hypothermic temperatures for transport
and/or storage of the organ.

[0016] The restoring of organ viability may be accomplished by restoring
high energy nucleotide (e.g., adenosine triphosphate (ATP)) levels and
enzyme levels in the organ, which were reduced by warm ischemia time
and/or hypoxia, by perfusing the organ with an oxygenated medical fluid,
such as an oxygenated cross-linked hemoglobin-based bicarbonate medical
fluid, at normothermic or near-normothermic temperatures. The organ may
be flushed with a medical fluid prior to perfusion with the oxygenated
medical fluid. Such perfusion can be performed at either normothermic or
hypothermic temperatures, preferably at hypothermic temperatures. For
hypothermic flush, static storage and hypothermic perfusion, the medical
fluid preferably contains little or no oxygen and preferably includes
antioxidants, both molecular (e.g., 2-ascorbic acid tocopherol) and
enzymatic (e.g., catalase and superoxide dismutase (SOD)). Normothermic
and/or hypothermic perfusion, and preferably hypothermic perfusion, can
be performed in vivo as well as in vitro. Such perfusion arrests ischemic
injury in preparation for transport, storage and/or transplant of the
organ.

[0017] The normothermic treatment is preferably employed after an organ
has been subjected to hypothermic temperatures, statically and/or under
perfusion. Such initial hypothermic exposure can occur, for example,
during transport and/or storage of an organ after harvesting. The
treatment is also suitable for organs that will ultimately be stored
and/or transported under hypothermic conditions. In other words, the
treatment can be applied to organs prior to cold storage and/or
transport.

[0018] In the normothermic perfusion mode, gross organ perfusion pressure
is preferably provided by a pneumatically pressurized medical fluid
reservoir controlled in response to a sensor disposed in an end of tubing
placed in the organ, which may be used in combination with a stepping
motor/cam valve or pinch valve which provides for perfusion pressure fine
tuning, prevents overpressurization and/or provides emergency flow
cut-off. Alternatively, the organ may be perfused directly from a pump,
such as a roller pump or a peristaltic pump, with proper pump control
and/or sufficiently fail-safe controllers to prevent overpressurization
of the organ, especially as a result of a system malfunction.
Substantially eliminating overpressurization prevents and/or reduces
damage to the vascular endothelial lining and to the organ tissue in
general. Viability of the organ may be monitored, preferably
automatically, in the normothermic perfusion mode, preferably by
monitoring organ resistance (pressure/flow) and/or pH, pO2,
pCO2, LDH, T/GST, Tprotein, lactate, glucose, base excess and/or
ionized calcium levels in the medical fluid that has been perfused
through the organ and collected.

[0019] An organ viability index may be provided taking into account the
various measured factors identified above, such as vascular resistance,
pH etc. The index may be organ specific, or may be adaptable to various
organs. The index compiles the monitored parameters into a diagnostic
summary to be used for making organ therapy decisions and deciding
whether to transplant the organ. The index may be automatically generated
and provided to the physician.

[0020] Normothermic perfusion may be preceded by and/or followed by
hypothermic perfusion. In the hypothermic mode, the organ is perfused
with a medical fluid containing substantially no oxygen, preferably a
simple crystalloid solution that may preferably be augmented with
antioxidants, intermittently or at a slow continuous flow rate.
Hypothermic perfusion also can be performed in vivo as well as in vitro
prior to removal of the organ from the donor. Hypothermic perfusion
reduces the organ's metabolic rate, allowing the organ to be preserved
for extended periods of time. The medical fluid is preferably fed into
the organ by pressure from an intermediary tank which has a low pressure
head so overpressurization of the organ is avoided. Alternatively, in
embodiments, gravity can be used to feed the medical fluid into the organ
from the intermediary tank, if appropriate. Alternatively, the organ may
be perfused directly from a pump, such as a roller pump or a peristaltic
pump, with proper pump control and/or sufficiently fail-safe controllers
to prevent overpressurization of the organ, especially as a result of a
system malfunction. Substantially eliminating overpressurization prevents
or reduces damage to the vascular endothelial lining of the organ and to
the organ tissue in general, in particular at hypothermic temperatures
when the organ has less ability to protect itself by vascular
constriction. Viability of the organ may also be monitored, preferably
automatically, during the recovery process, preferably by monitoring
organ resistance (pressure/flow) and/or pH, pO2, pCO2, LDH,
T/GST, Tprotein, lactate, glucose, base excess and/or ionized calcium
levels in the medical fluid that has been perfused through the organ and
collected.

[0021] Embodiments of this invention include a control system for
automatically controlling perfusion of one or more organs by selecting
between perfusion modes and control parameters. Automatic perfusion may
be based on sensed conditions in the system or manually input parameters.
The system may be preprogrammed or programmed during use. Default values
and viability checks are utilized.

[0022] The perfusion apparatus may be used for various organs, such as the
kidneys, and may be adapted to more complex organs, such as the liver,
having multiple vasculature structures, for example, the hepatic and
portal vasculatures of the liver.

[0023] An organ diagnostic apparatus may also be provided to produce
diagnostic data such as an organ viability index. The organ diagnostic
apparatus includes features of an organ perfusion apparatus, such as
sensors and temperature controllers, as well as cassette interface
features, and provides analysis of input and output fluids in a perfusion
system. Typically, the organ diagnostic apparatus is a simplified
perfusion apparatus providing diagnostic data in a single pass, in-line
perfusion.

[0024] The present invention also provides an organ cassette which allows
an organ to be easily and safely moved between apparatus for perfusing,
storing, analyzing and/or transporting the organ. The organ cassette may
be configured to provide uninterrupted sterile conditions and efficient
heat transfer during transport, recovery, analysis and storage, including
transition between the transporter, the perfusion apparatus and the organ
diagnostic apparatus.

[0025] The present invention also provides an organ transporter which
allows for transportation of an organ over long distances. The organ
transporter may be used for various organs, such as the kidneys, and may
be adapted to more complex organs, such as the liver, having multiple
vasculature structures, for example, the hepatic and portal vasculatures
of the liver. The organ transporter includes features of an organ
perfusion apparatus, such as sensors and temperature controllers, as well
as cassette interface features.

[0026] The perfusion apparatus, transporter, cassette, and organ
diagnostic apparatus may be networked to permit remote management,
tracking and monitoring of the location and therapeutic and diagnostic
parameters of the organ or organs being stored or transported. The
information systems may be used to compile historical data of organ
transport and storage, and provide cross-referencing with hospital and
United Network for Organ Sharing (UNOS) data on the donor and recipient.
The systems may also provide outcome data to allow for ready research of
perfusion parameters and transplant outcomes.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] These and other aspects and advantages of the invention will become
apparent from the following detailed description of embodiments when
taken in conjunction with the accompanying drawings, in which:

[0028]FIG. 1 is an organ perfusion apparatus according to the invention;

[0051]FIG. 24 shows data structures and information transfer schemes of a
perfusion and organ transplant system of the present invention;

[0052] FIGS. 25 and 25A show motor control of a perfusion pump according
to the present invention;

[0053] FIG. 26 shows a liver perfusion apparatus according to the present
invention;

[0054] FIG. 27 shows a close-up view of a peristaltic pump for use in a
perfusion apparatus according to FIG. 26;

[0055] FIG. 28 shows an overall view of an organ diagnostic system
according to the present invention;

[0056]FIG. 29 shows a perspective view of an organ evaluation instrument
for use in an organ diagnostic system according to FIG. 28;

[0057] FIG. 30 shows an in-line perfusion system for use in an organ
diagnostic system according to FIG. 28; and

[0058] FIG. 31 shows a logic circuit for an organ diagnostic system
according to FIG. 28.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0059] For a general understanding of the features of the invention,
reference is made to the drawings. In the drawings, like reference
numerals have been used throughout to designate like elements.

[0060]FIG. 1 shows an organ perfusion apparatus 1 according to the
invention. FIG. 2 is a schematic illustration of the apparatus of FIG. 1.
The apparatus 1 is preferably at least partially microprocessor
controlled, and pneumatically actuated. The microprocessor 150 connection
to the sensors, valves, thermoelectric units and pumps of the apparatus 1
is schematically shown in FIG. 3. Microprocessor 150 and apparatus 1 may
be configured to and are preferably capable of further being connected to
a computer network to provide data sharing, for example across a local
area network or across the Internet.

[0061] The organ perfusion apparatus 1 is capable of perfusing one or more
organs simultaneously, at both normothermic and hypothermic temperatures
(hereinafter, normothermic and hypothermic perfusion modes). All medical
fluid contact surfaces are preferably formed of or coated with materials
compatible with the medical fluid used, more preferably non-thrombogenic
materials. As shown in FIG. 1, the apparatus 1 includes a housing 2 which
includes front cover 4, which is preferably translucent, and a reservoir
access door 3. The apparatus preferably has one or more control and
display areas 5a, 5b, 5c, 5d for monitoring and controlling perfusion.

[0062] As schematically shown in FIG. 2, enclosed within the housing 2 is
a reservoir 10 which preferably includes three reservoir tanks 15a, 15b,
17. Two of the reservoir tanks 15a, 15b are preferably standard one liter
infusion bags, each with a respective pressure cuff 16a, 16b. A pressure
source 20 can be provided for pressurizing the pressure cuffs 16a, 16b.
The pressure source 20 is preferably pneumatic and may be an on board
compressor unit 21 supplying at least 10 LPM external cuff activation via
gas tubes 26,26a,26b, as shown in FIG. 2. The invention, however, is not
limited to use of an on board compressor unit as any adequate pressure
source can be employed, for example, a compressed gas (e.g., air,
CO2, oxygen, nitrogen, etc.) tank (not shown) preferably with a tank
volume of 1.5 liters at 100 psi or greater for internal pressurization.
Alternatively, an internally pressurized reservoir tank (not shown) may
be used. Reservoir tanks 15a, 15b, 17 may, in embodiments, be bottles or
other suitably rigid reservoirs that can supply perfusate by gravity or
can be pressurized by compressed gas.

[0063] Gas valves 22-23 are provided on the gas tube 26 to allow for
control of the pressure provided by the onboard compressor unit 21.
Anti-back flow valves 24a, 24b may be provided respectively on the gas
tubes 26a, 26b. Pressure sensors P5, P6 may be provided respectively on
the gas tubes 26a, 26b to relay conditions therein to the microprocessor
150, shown in FIG. 3. Perfusion, diagnostic and/or transporter apparatus
may be provided with sensors to monitor perfusion fluid pressure and flow
in the particular apparatus to detect faults in the particular apparatus,
such as pressure elevated above a suitable level for maintenance of the
organ. Gas valves GV1 and GV2 may be provided to release
pressure from the cuffs 16a, 16b. One or both of gas valves GV1 and
GV2 may be vented to the atmosphere. Gas valve GV4 in
communication with reservoir tanks 15a, 15b via tubing 18a, 18b may be
provided to vent air from the reservoir tanks 15a, 15b through tubing 18.
Tubing 18, 18a, 18b, 26, 26a and/or 26b may be configured with filters
and/or check valves to prevent biological materials from entering the
tubing or from proceeding further along the fluid path. The check valves
and/or filters may be used to prevent biological materials from leaving
one organ perfusion tubeset and being transferred to the tubeset of a
subsequent organ in a multiple organ perfusion configuration. The check
valves and/or filters may also be used to prevent biological materials,
such as bacteria and viruses, from being transferred from organ to organ
in subsequent uses of the perfusion apparatus in the event that such
biological materials remain in the perfusion apparatus after use. The
check valves and/or filters prevent contamination problems associated
with reflux in the gas and/or vent lines. For example, the valves may be
configured as anti-reflux valves to prevent reflux. The third reservoir
tank 17 is preferably pressurized by pressure released from one of the
pressure cuffs via gas valve GV2.

[0064] The medical fluid is preferably synthetic and may, for example, be
a simple crystalloid solution, or may be augmented with an appropriate
oxygen carrier. The oxygen carrier may, for example, be washed,
stabilized red blood cells, cross-linked hemoglobin, pegolated hemoglobin
or fluorocarbon based emulsions. The medical fluid may also contain
antioxidants known to reduce peroxidation or free radical damage in the
physiological environment and specific agents known to aid in tissue
protection. As discussed in detail below, an oxygenated (e.g.,
cross-linked hemoglobin-based bicarbonate) solution is preferred for the
normothermic mode while a non-oxygenated (e.g., simple crystalloid
solution preferably augmented with antioxidants) solution is preferred
for the hypothermic mode. The specific medical fluids used in both the
normothermic and hypothermic modes are designed to reduce or prevent the
washing away of or damage to the vascular endothelial lining of the
organ. For the hypothermic perfusion mode, as well as for flush and/or
static storage, a preferred solution is the solution disclosed in U.S.
patent application Ser. No. 09/628,311, filed Jul. 28, 2000, the entire
disclosure of which is incorporated herein by reference. Examples of
additives which may be used in perfusion solutions for the present
invention are also disclosed in U.S. Pat. No. 6,046,046 to Hassanein, the
entire disclosure of which is incorporated by reference. Of course, other
suitable solutions and materials may be used, as is known in the art.

[0065] The perfusion solution may be provided in a perfusion solution kit,
for example, a saleable package preferably containing at least one first
container holding a first perfusion solution for normothermic perfusion
and at least one second container holding a second, different perfusion
solution for hypothermic perfusion, optionally the box 10 shown in FIG.
2. The first perfusion solution may contain at least one oxygen carrier,
may be oxygenated and/or may be selected from the group consisting of a
cross-linked hemoglobin and stabilized red blood cells. The second
perfusion solution may be non-oxygenated, may contain at least one
anti-oxidant, and/or may contain at least one vasodilator. Additionally,
the solution preferably contains no more than 5 mM of dissolved pyruvate
salt. Also, the first container and the second container may be
configured to be operably connected to a perfusion machine as perfusion
fluid reservoirs in fluid communication with perfusate conduits of said
perfusion machine. Further, one of the first and second containers may be
compressible to apply pressure to the perfusion solution therein.
Furthermore, at least one of the first and second containers may include
a first opening for passage of a contained perfusion solution out of the
container and a second opening passage of a compressed gas into the
container. The package may be a cassette configured to be operably
connected to a perfusion machine for connection of the first and second
containers within the cassette in fluid communication with perfusate
conduits or tubing of the perfusion machine.

[0066] In other embodiments, the perfusion solution kit may contain at
least one first container holding a first perfusion solution for
hypothermic perfusion at a first temperature and at least one second
container holding a second, different perfusion solution for hypothermic
perfusion at a second temperature lower than the first temperature. In
the kit, the first perfusion solution may contain at least a crystalloid
and may contain at least one vasodilator. The second perfusion solution
may be oxygen carrier enhanced, where the oxygen carrier is selected from
the group consisting of a hemoglobin and stabilized red blood cells. In
addition, the second perfusion solution may, if desired, contain at least
one anti-oxidant or free radical scavenger. Preferably, the second
solution contains no more than 5 mM of dissolved pyruvate salt. As above,
the first container and the second container may be configured to be
operably connected to a perfusion machine as perfusion fluid reservoirs
in fluid communication with perfusate conduits of said perfusion machine.
Further, one of the first and second containers may be compressible to
apply pressure to the perfusion solution therein. Furthermore, at least
one of the first and second containers may include a first opening for
passage of a contained perfusion solution out of the container and a
second opening passage of a compressed gas into the container. The
package may be a cassette configured to be operably connected to a
perfusion machine for connection of the first and second containers
within the cassette in fluid communication with perfusate conduits or
tubing of the perfusion machine.

[0067] The medical fluid within reservoir 10 is preferably brought to a
predetermined temperature by a first thermoelectric unit 30a in heat
transfer communication with the reservoir 10. A temperature sensor T3
relays the temperature within the reservoir 10 to the microprocessor 150,
which adjusts the thermoelectric unit 30a to maintain a desired
temperature within the reservoir 10 and/or displays the temperature on a
control and display areas 5a for manual adjustment. Alternatively or in
addition, and preferably where the organ perfusion device is going to be
transported, the medical fluid within the hypothermic perfusion fluid
reservoir can be cooled utilizing a cryogenic fluid heat exchanger
apparatus such as that disclosed in co-pending application Ser. No.
09/039,443, which is hereby incorporated by reference.

[0068] An organ chamber 40 is provided which supports a cassette 65, as
shown in FIG. 2, which holds an organ to be perfused, or a plurality of
cassettes 65,65,65, as shown in FIG. 12, preferably disposed one adjacent
the other. Various embodiments of the cassette 65 are shown in FIGS.
11A-11D. The cassette 65 is preferably formed of a material that is light
but durable so that the cassette 65 is highly portable. The material may
also be transparent to allow visual inspection of the organ.

[0069] Preferably the cassette 65 includes side walls 67a, a bottom wall
67b and an organ supporting surface 66, which is preferably formed of a
porous or mesh material to allow fluids to pass therethrough. The
cassette 65 may also include a top 67d and may be provided with an
opening(s) 63 for tubing (see, for example, FIG. 11D). The opening(s) 63
may include seals 63a (e.g., septum seals or o-ring seals) and optionally
be provided with plugs (not shown) to prevent contamination of the organ
and maintain a sterile environment. Also, the cassette 65 may be provided
with a closeable air vent 61 (see, for example, FIG. 11D). Additionally,
the cassette 65 may be provided with tubing for connection to the organ
or to remove medical fluid from the organ bath and a connection device(s)
64 for connecting the tubing to, for example, tubing 50c, 81, 82, 91
and/or 132 (see, for example, FIG. 11D). The cassette 65, and more
particularly the organ support, opening(s), tubing(s) and/or
connection(s), may be specifically tailored to the type of organ and/or
size of organ to be perfused. Outer edges 67c of the side support walls
67a can be used to support the cassette 65 disposed in the organ chamber
40. The cassette 65 may further include a handle portion 68 which allows
the cassette 65 to be easily handled, as shown, for example, in FIGS. 11C
and 11D. Each cassette 65 may also be provided with its own stepping
motor/cam valve 75 (for example, in the handle portion 68, as shown in
FIG. 11c) for fine tuning the pressure of medical fluid perfused into the
organ 60 disposed therein, discussed in more detail below. Alternatively,
pressure may, in embodiments, be controlled by way of a pneumatic
chamber, such as an individual pneumatic chamber for each organ (not
shown), or by any suitable variable valve such as a rotary screw valve or
a helical screw valve.

[0070]FIG. 17 shows an alternative embodiment of cassette 65. In FIG. 17,
cassette 65 is shown with tubeset 400. Tubeset 400 can be connected to
perfusion apparatus 1 or to an organ transporter or an organ diagnostic
apparatus, and allows cassette 65 to be moved between various apparatus
without jeopardizing the sterility of the interior of cassette 65.
Preferably, cassette 65 is made of a sufficiently durable material that
it can withstand penetration and harsh impact. Cassette 65 is provided
with a lid, preferably two lids, an inner lid 410 and an outer lid 420.
The lids 410 and 420 may be removable or may be hinged or otherwise
connected to the body of cassette 65. Clasp 405 provides a mechanism to
secure rids 410 and 420 to the top of cassette 65. Clasp 405 may
additionally be configured with a lock to provide further security and
stability. A biopsy port 430 may additionally be included in inner lid
410 or both inner lid 410 and outer lid 420. Biopsy port 430 provides
access to the organ to allow for additional diagnosis of the organ with
minimal disturbance of the organ. Cassette 65 may also have an overflow
trough 440 (shown in FIG. 17A). Overflow trough 440 is a channel present
in the top of cassette 65. When lids 410 and 420 are secured on cassette
65, overflow trough 440 provides a region that is easy to check to
determine if the inner seal is leaking. Perfusate may be poured into and
out of cassette 65 and may be drained from cassette 65 through a stopcock
or removable plug.

[0071] Cassette 65 and/or both lids 410 and 420 may be constructed of an
optically clear material to allow for viewing of the interior of cassette
65 and monitoring of the organ and to allow for video images or
photographs to be taken of the organ. Perfusion apparatus 1 or cassette
65 may be wired and fitted with a video camera or a photographic camera,
digital or otherwise, to record the progress and status of the organ. The
captured images may be made available over a computer network such as a
local area network or the Internet to provide for additional data
analysis and remote monitoring. Cassette 65 may also be provided with a
tag that would signal, e.g., through a bar code, magnetism, radio
frequency, or other means, the location of the cassette, that the
cassette is in the apparatus, and/or the identity of the organ to the
perfusion apparatus or transporter. Cassette 65 may be sterile packaged
and/or may be packaged or sold as a single-use disposable cassette, such
as in a peel-open pouch. A single-use package containing cassette 65 may
also include tubeset 400.

[0072] Cassette 65 may additionally be provided with an organ chair 1800
shown in FIGS. 18 and 18A. Organ chair 1800 is removable and provides a
support surface for the organ within cassette 65. Utilizing a removable
organ chair 1800 allows the organ to be cannulated and secured under cold
conditions when the organ is recovered from a donor before being placed
into cassette 65. Organ chair 1800 may be reusable or single-use. Organ
chair 1800 may be constructed specifically to correspond to each type of
organ, such as the kidney, heart or liver. Organ chair 1800 is preferably
designed to be form fitting to the organ but to allow for the full
anthropometric range of organ sizes.

[0073] Preferably, organ chair 1800 is at least partially perforated to
allow fluids to pass through organ chair 1800. The perforations in organ
chair 1800 may be sized to catch organ debris, or an additional filter
layer, preferably constructed of cloth, fabric, nylon, plastic, etc., to
catch organ debris of at least 15 microns in diameter. In addition, a
separate filter may be used on the tubing that intakes fluid directly
from the perfusate bath to prevent organ debris of a predetermined size,
for example at least 10 to 15 microns in diameter, from entering the
perfusion tubing.

[0074] Organ chair 1800 may also be configured with a venous outflow
sampler 1810. Organ chair 1800 funnels the venous outflow into venous
outflow sampler 1810. Venous outflow sampler 1810 provides a readily
available source for capturing the venous outflow of the organ. Capturing
the venous outflow in this manner permits analysis of the perfusate
leaving the organ without cannulating a vein and enables organ viability
to be measured with a high degree of sensitivity by analyzing
differentially the perfusate flowing into and out of the organ.
Alternatively, venous outflow may be captured directly by cannulating a
vein, but this method increases the risk of damaging the vein or the
organ. Organ chair 1800 may also be raised and lowered within cassette 65
to facilitate sampling from venous outflow sampler 1810. Alternatively, a
sufficient amount of the organ bath may be drained from cassette 65 to
obtain'access to venous outflow sampler 1810 or to capture venous outflow
before the outflow mixes with the rest of the perfusate in the organ
bath.

[0075] Organ chair 1800 is preferably additionally configured with a
cannula 1820 that attaches to the perfused artery, such as the renal
artery. Cannula 1820 may be reusable or may be suitable for single-use,
preferably provided in a sterile package with cassette 65, organ chair
1800 and tubeset 400. Cannula 1820 is provided with a cannula clamp 1830
to secure cannula 1820 around the perfused artery and to preferably
provide leak-tight perfusion. A straight-in flanged cannula may also be
used, however clamping around the artery is preferable to prevent contact
with the inner surface of the artery, which is easily damaged. Cannula
1820 may also be configured with additional branching connections for
accessory arteries. Multiple cannula and cannula clamp sizes may be used
to accommodate various artery sizes or an adjustable cannula and cannula
clamp may be used to accommodate various sized arteries. Cannula clamp
1830 may be a clam-shell configuration or may be a two-part design.
Cannula clamp 1830 may be configured with integral or separate means for
tightening cannula clamp 1830 to the proper pressure to provide
leak-tight perfusion. In addition, cannula 1820 may be provided with a
snap 1840 to hold cannula 1820 closed. Cannula 1820 may also be provided
with a vent 1850 to remove air bubbles from cannula 1820.

[0076] Organ chair 1809 preferably has a detented region 1860 that
corresponds to protrusions 1870 on cannula 1820. Such detents, tracks or
grooves on organ chair 1800 allow cannula 1820 to be positioned at
several locations to provide various tensions on the perfused artery.
This allows the ideal minimum tension to be set for each artery. Cannula
clamp 1830 secures the perfusate tubing to the perfused artery. Cannula
1820 is adjustably secured to organ chair 1800 to provide for positioning
the perfused artery to accommodate variations in organ size and artery
length to prevent stretching, twisting, sagging or kinking of the artery.
The combination of organ chair 1800, cannula 1820 and additional straps
or wide belts provides a secure platform to transport the organ and to
transfer the organ between the cassette and the surgical field.

[0078] The cassette 65 is configured such that it may be removed from the
organ perfusion apparatus 1 and transported to another organ perfusion
apparatus in a portable transporter apparatus, such as, for example, a
conventional cooler or a portable container such as that disclosed in
simultaneously filed co-pending U.S. application Ser. No. 09/161,919, or
U.S. Pat. No. 5,586,438 to Fahy, which are hereby incorporated by
reference in their entirety.

[0079] In embodiments, when transported, the organ is disposed on the
organ supporting surface 66 and the cassette 65 is preferably enclosed in
a preferably sterile bag 69, as shown, for example, in FIG. 11A. When the
organ is perfused with medical fluid, effluent medical fluid collects in
the bag 69 to form an organ bath. Alternatively, the cassette 65 can be
formed with a fluid tight lower portion in which the effluent medical
fluid may collect, or the effluent medical fluid may collect in the organ
chamber 40 to form the organ bath. In either alternative case, the bag 69
would preferably be removed prior to inserting the cassette into the
organ chamber 40. Further, where a plurality of organs are to be
perfused, an organ chamber may be provided for each organ. Alternatively,
cassette 65 can be transported in the dual-lid cassette of FIG. 17 and
additionally carried within a portable organ transporter.

[0080] FIG. 19 shows an external view of an embodiment of transporter 1900
of the invention. The transporter 1900 of FIG. 19 has a stable base to
facilitate an upright position and handles 1910 for carrying transporter
1900. Transporter 1900 may also be fitted with a shoulder strap and/or
wheels to assist in carrying transporter 1900. A control panel 1920 is
preferably also provided. Control panel 1920 may display characteristics,
such as, but not limited to infusion pressure, power on/off, error or
fault condition, flow rate, flow resistance, infusion temperature, bath
temperature, pumping time, battery charge, temperature profile (maximums
and minimums), cover open or closed, history log or graph, and additional
status details and messages, which are preferably further transmittable
to a remote location for data storage and/or analysis. Flow and pressure
sensors or transducers in transporter 1900 may be used to calculate
various organ characteristics including pump pressure and vascular
resistance of an organ, which can be stored in computer memory to allow
for analysis of, for example, vascular resistance history, as well as to
detect faults in the apparatus, such as elevated pressure.

[0081] Transporter 1900 has latches 1930 that require positive user action
to open, thus avoiding the possibility that transporter 1900
inadvertently opens during transport. Latches 1930 hold top 1940 in place
on transporter 1900. Top 1940 or a portion thereof may be constructed
with an optically clear material to provide for viewing of the cassette
and organ perfusion status. Transporter 1900 may be configured with a
cover open detector that monitors and displays if the cover is open or
closed. Transporter 1900 may be configured with an insulating exterior of
various thicknesses to allow the user to configure transporter 1900 for
varying extents and distances of transport. In embodiments, compartment
1950 may be provided to hold patient and organ data such as charts,
testing supplies, additional batteries, hand-held computing devices
and/or other accessories for use with transporter 1900. Transporter 1900
may also be configured with means for displaying a UNOS label and/or
identification and return shipping information.

[0082] FIG. 20 shows a cross-section view of a transporter 1900.
Transporter 1900 contains cassette 65 and pump 2010. Cassette 65 may be
placed into and taken out of transporter 1900 without disconnecting
tubeset 400 from cassette 65, thus maintaining sterility of the organ.
Sensors in transporter 1900 can detect the presence of cassette 65 in
transporter 1900, and depending on the sensor, can read the organ
identity from a barcode or radio frequency or other smart tag that may be
integral to cassette 65. This allows for automated identification and
tracking of the organ and helps monitor and control the chain of custody.
A global positioning system may be added to transporter 1900 and/or
cassette 65 to facilitate tracking of the organ. Transporter 1900 can be
interfaced to a computer network by hardwire connection to a local area
network or by wireless communication while in transit. This interface
allows perfusion parameters, vascular resistance, and organ
identification and transporter and cassette location to be tracked and
displayed in real-time or captured for future analysis.

[0083] Transporter 1900 also preferably contains a filter 2020 to remove
sediment and other particulate matter, preferably ranging in size from
0.05 to 15 microns in diameter or larger, from the perfusate to prevent
clogging of the apparatus or the organ. Transporter 1900 also contains
batteries 2030, which may be located at the bottom of transporter 1900 or
beneath pump 2010 or at any other location that provides easy access to
change batteries 2030. Batteries 2030 may be rechargeable outside of
transporter 1900 or while intact within transporter 1900 and/or are
preferably hot-swappable one at a time. Batteries 2030 are preferably
rechargeable rapidly and without full discharge. Transporter 1900 may
also provide an additional storage space 2040 at the bottom of
transporter 1900 for power cords, batteries and other accessories.
Transporter 1900 may also include a power port for a DC hookup to a
vehicle such as an automobile or airplane and/or for an AC hookup.

[0084]FIG. 21 shows a block diagram of transporter 1900. Transporter 1900
of FIG. 21 is intended to provide primarily hypothermic perfusion, and
may operate at any temperatures, for example in the range of -25 to
60° C., approximately 0 to 8° C., preferably approximately
4° C. The temperature may be adjusted based on the particular
fluids used and adapted to the particular transport details, such as
length of time of transport. Transporter 1900 is cooled by coolant 2110,
which may be an ice and water bath or a cryogenic material. In
embodiments using cryogenic materials, the design should be such that
organ freezing is prevented. The temperature of the perfusate bath
surrounding the organ is monitored by temperature transducer 2115.
Transporter 1900 also contains filters 2020 to remove sediment and
particulate, ranging in size from 0.05 to 15 microns in diameter or
larger, from the perfusate to prevent clogging of the apparatus or the
organ. Using a filter 2020 downstream of pump 2010 allows for capturing
inadvertent pump debris and also dampens pressure spikes from pump 2010.

[0085] The flow of perfusate within transporter 1900 is controlled by pump
2010, which is preferably a peristaltic or roller pump. Pump 2010 is
preferably not in contact with the perfusate to help maintain sterility.
In addition, tubeset 400 may be attached to pump 2010 without opening the
tubing circuit. Pump 2010 is controlled by a computer or microcontroller.
The computer can actively modulate the angular velocity of pump 2010 to
reduce the natural pulse actions of pump 2010 to a low level, resulting
in essentially non-pulsatile flow. Further computer control can impose a
synthesized pressure pulse profile that can be sinusoidal or
physiological or otherwise. The average flow rate and pressure can be
made independent of pulse repetition rate by pulse width modulating or
amplitude modulating the synthesized pressure pulses. Control over some
or all of the pulse parameters can be made available to users through
control panel 1920 or over a network. Pulse control can be organ
specific. In the case of a liver, a single pump can provide continuous
flow to the portal vein at, for example, 1 to 3 liters per minute while
providing pulsatile flow to the hepatic artery at, for example, 100 to
300 ml per minute. Synchronizing the shunt valves to the pump controller
allows independent pressure regulation of the two flows.

[0086] The flow of the perfusate into the organ is monitored by flow
sensor 2125. Pressure transducers 2120 may be present to monitor the
pressure the perfusate places on the tubing. Pressure transducers 2120
may be used to monitor the pump pressure and/or the infusion pressure. A
pressure transducer 2120 may be present just upstream of the organ to
monitor the organ infusion pressure. Transporter 1900 may be configured
with a bubble detector 2125 to detect bubbles before the perfusate enters
bubble trap 2130. Bubble detectors, such as bubble detector 2125, may be
used to detect bubbles in, for example, the infuse line and/or in the
pump output line. Bubble trap 2139 removes air bubbles from the perfusate
and vents the bubbles into the wash tube. Bubble trap 2130 may be
disposable and may be constructed integral to tubeset 400. Perfusate
exiting bubble trap 2130 can either continue through infuse valve 2140 or
wash valve 2150. Wash valve 2150 is normally open and infuse valve 2140
is normally closed. Preferably, wash valve 2150 and infuse valve 2140
operate dependently in an on/off manner, such that if one valve is open,
the other valve is closed. Although infuse valve 2140 is normally closed,
if the sensor and monitors all report suitable perfusion parameters
present in transporter 1900, then infuse valve 2140 may be opened to
allow organ perfusion. In the occurrence of a fault, such as elevated
perfusion pressure above a suitable level for the organ, infuse valve
2140 switches back to closed and wash valve 2150 is opened to divert
fluid flow into the perfusate bath surrounding the organ. This provides a
failsafe mechanism that automatically shunts perfusate flow and prevents
organ perfusion in case of a power failure or computer or electronics
malfunction. A pressure transducer 2120, such as designated by P2,
may be hardwired, redundant to the computer and software control, to wash
valve 2150 and infuse valve 2140 to quickly deliver a default message to
the valves in the case of a pressure malfunction. In embodiments, the
diverted fluid may be separately collected in another container or
compartment.

[0087] FIG. 22 shows various operation states of transporter 1900. For
example, using the controls provided on control panel 1920, a user may
select operations such as perfuse, idle, wash and prime. FIG. 22 shows
various options depending on the present state of transporter 1900. The
labels idle, prime, wash, perfuse and error handling indicate the state
of transporter 1900 that is preferably displayed on control panel 1920
during the corresponding operation. For example, when transporter 1900 is
in a wash operation, control panel 1920 displays the wash operation
indicator, such as an LED display. The arrows connecting the various
operations of transporter 1900 indicate the manual and automatic actions
that may occur to transition transporter 1900 between operation states.
Manual actions require the user to act, for example by pressing a button
or turning a knob or dial. FIG. 22 exemplifies pressing a button or other
indicator, for example, to move from a perfusion operation to an idle
operation by pressing the stop button (Press Stop). To move directly into
a perfuse operation from an idle operation, a user presses the perfuse
button (Press Perfuse).

[0088] Automatic operations may be controlled by the passage of time
and/or by an internal monitor within transporter 1900. Such automatic
operation is shown in FIG. 22, for example, connecting the prime
operation to the idle operation. If the prime operation has been
completed according to the internal transporter program parameters before
the wash button has been pressed, transporter 1900 returns to an idle
operation. Another automatic operation occurs during a perfuse operation
if a fault or error occurs, such as overpressurization of the organ. When
an error or fault occurs, transporter 1900 can move to an error handling
operation to determine the extent or degree of the fault or error. If the
fault or error is determined to be a small or correctable error,
transporter 1900 moves into a wash operation. If transporter 1900 can
then adjust the system parameters to handle the fault or error,
transporter 1900 moves back to perfuse (Error Recovery). If transporter
1900 can not adjust the system parameters to handle the fault or error,
transporter 1900 moves to an idle operation. If the error or fault
detected is determined to be substantial, tranporter 1900 may move
directly into an idle operation.

[0089]FIG. 23 shows an alternative cross-section of transporter 1900.
Transporter 1900 may have an outer enclosure 2310 constructed of metal,
or preferably a plastic or synthetic resin that is sufficiently strong to
withstand penetration and impact. Transporter 1900 contains insulation
2320, preferably a thermal insulation made of, for example, glass wool or
expanded polystyrene. Insulation 2320 may be various thicknesses ranging
from 0.5 inches to 5 inches thick or more, preferably 1 to 3 inches, such
as approximately 2 inches thick. Transporter 1900 is cooled by coolant
2110, which may be, e.g., an ice and water bath or a cryogenic material.
In embodiments using cryogenic materials, the design should be such that
organ freezing is prevented. An ice and water mixture is preferably in an
initial mixture of approximately 1 to 1, however, in embodiments the ice
and water bath may be frozen solid. Transporter 1900 can be configured to
hold various amounts of coolant, preferably up to 10 to 12 liters. An ice
and water bath is preferable because it is inexpensive and can not get
cold enough to freeze the organ. Coolant 2110 preferably lasts for a
minimum of 6 to 12 hours and more preferably lasts for a minimum of 30 to
50 hours without changing coolant 2110. The level of coolant 2110 may be
viewed through a transparent region of transporter 1900 or may be
automatically detected and monitored by a sensor. Coolant 2110 can be
replaced without stopping perfusion or removing cassette 65 from
transporter 1900. Coolant 2110 is maintained in a watertight compartment
2115 of transporter 1900. Compartment 2115 prevents the loss of coolant
2110 in the event transporter 1900 is tipped or inverted. Heat is
conducted from the walls of the perfusion reservoir and cassette 65 into
coolant 2110 enabling control within the desired temperature range.
Coolant 2110 is a failsafe cooling mechanism because transporter 1900
automatically reverts to cold storage in the case of power loss or
electrical or computer malfunction. Transporter 1900 may also be
configured with a heater to raise the temperature of the perfusate.

[0090] Transporter 1900 may be powered by batteries or by electric power
provided through plug 2330. An electronics module 2335 is also provided
in transporter 1900. Electronics module 2335 is cooled by vented air
convection 2370, and may further be cooled by a fan. Preferably,
electronic module 2335 is positioned separate from the perfusion tubes to
prevent the perfusate from wetting electronics module 2335 and to avoid
adding extraneous heat from electronics module 2335 to the perfusate.
Transporter 1900 has a pump 2010 that provides pressure to perfusate
tubing 2360 to deliver perfusate 2340 to organ 2350. Transporter 1900 may
be used to perfuse various organs such as a kidney, heart, liver, small
intestine and lung. Transporter 1900 and cassette 65 may accommodate
various amounts of perfusate 2340, for example up to 3 to 5 liters.
Preferably, approximately 1 liter of a hypothermic perfusate 2340 is used
to perfuse organ 2350. Organ 2350 may be various organs, including but
not limited to a kidney, heart, lung, liver or small intestine.

[0091] Cassette 65 and transporter 1900 are preferably constructed to fit
or mate such that efficient heat transfer is enabled. The geometric
elements of cassette 65 and transporter 1900 are preferably constructed
such that when cassette 65 is placed within transporter 1900, the
elements are secure for transport.

[0092]FIG. 24 shows various data structures and information connections
that can be facilitated to assist in the overall communication and data
transfers that may be beneficial before, during and after organ
transplantation. The perfusion apparatus, transporter, cassette, and
organ diagnostic apparatus may be networked to permit remote management,
tracking and monitoring of the location and therapeutic and diagnostic
parameters of the organ or organs being stored or transported. The
information systems may be used to compile historical data of organ
transport and storage, and provide cross-referencing with hospital and
UNOS data on the donor and recipient. The systems may also provide
outcome data to allow for ready research of perfusion parameters and
transplant outcomes. For example, information regarding the donor may be
entered at the location where an organ is recovered from a donor.
Information may also be directly recovered from the perfusion, diagnostic
or transporter apparatus to monitor organ status and location. Various
types of information may be grouped into sub-records or sub-directories
to assist in data management and transfer. All the sub-records may be
combined to form an overall transplant record, which may be disseminated
to or retrievable by physicians, scientists or other organizations for
tracking and monitoring purposes.

[0093] Preferred embodiments of transporter 1900 can automatically log
much or all of the perfusion process data and transporter 1900 events
into an internal database. A radio frequency or barcode labeled tag or
the like for each cassette 65 allows transporter 1900 to reference the
data uniquely to each organ. When transporter 1900 reaches a docking
port, transporter 1900 can upload data to a main database computer over a
LAN. Transporter 1900 can also provide real-time status whenever
transporter 1900 is connected to the LAN. Transporter 1900 can also be
configured with a wireless communications setup to provide real-time data
transfer during transport. Perfusion apparatus 1 can also be connected to
the LAN and since perfusion apparatus is generally stationary, data
uploads can occur continuously and in real-time. The data can be
cross-referenced with UNOS data to utilize the UNOS data on organ
identification, donor condition, donor logistics, recipient logistics and
recipient outcomes. Data may be displayed and accessed on the Internet to
facilitate monitoring from any location.

[0094] Within the perfusion, diagnostic and/or transporter apparatus, the
organ bath is preferably cooled to a predetermined temperature by a
second thermoelectric unit 30b, as shown in FIG. 2, in heat transfer
communication with the organ chamber 40. Alternatively and preferably
where the organ perfusion device is going to be transported, the medical
fluid within reservoir 10 can be cooled utilizing a heat transfer device
such as an ice and water bath or a cryogenic fluid heat exchanger
apparatus such as that disclosed in co-pending application Ser. No.
09/039,443, which is hereby incorporated by reference. A temperature
sensor T2 within the organ chamber 40 relays the temperature of the organ
60 to the microprocessor 150, which adjusts the thermoelectric unit 30b
to maintain a desired organ temperature and/or displays the temperature
on the control and display areas 5c for manual adjustment.

[0095] Medical fluid may be fed from the bag 15a directly to an organ 60
disposed in the organ chamber 40 through tubing 50a,50b,50c or from bag
15b through tubing 50d,50e,50c by opening valve LV4 or LV3,
respectively. Conventional medical fluid bag and tubing connections may
be utilized. All tubing is preferably disposable, easily replaceable and
interchangeable. Further, all tubing is preferably formed of or coated
with materials compatible with the medical fluids used, more preferably
non-thrombogenic materials. An end of the tubing 50c is inserted into the
organ 60. The tubing may beconnected to the organ(s) with conventional
methods, for example, with sutures. The tubing may include a lip to
facilitate connection to the organ. Alternatively, cannula 1820 described
above may be used with or without connection to an organ chair 1800.
However, the specific methods and connection depend on the type of
organs(s) to be perfused.

[0096] The microprocessor 150 preferably controls the pressure source 20
in response to signals from the pressure sensor P1 to control the
pressure of the medical fluid fed into the organ 60. The microprocessor
150 may display the pressure on the control and display areas 5a,
optionally for manual adjustment. A fluid flow monitor F1 may also be
provided on the tubing 50c to monitor the flow of medical fluid entering
the organ 60 to indicate, for example, whether there are any leaks
present in the organ.

[0097] Alternatively, the medical fluid may be fed from the reservoir tank
17 via tubing 51 into an intermediary tank 70 preferably having a
pressure head of approximately 5 to 40 mm Hg. Medical fluid is then fed
by gravity or, preferably, pressure, from the intermediary tank 70 to the
organ 60 along tubing 50c by activating a valve LV6. A level sensor
71 may be provided in the intermediary tank 70 in order to, maintain the
pressure head. Where a plurality of organ chambers 40 and organs 60 are
provided, the organs 60 are connected in parallel to the reservoir 10
utilizing suitable tubing duplicative of that shown in FIG. 2. See, for
example, FIG. 12. The use of pneumatically pressurized and gravity fed
fluid pumps configured to avoid overpressurization even in cases of
system failure reduces or prevents general tissue damage to the organ and
the washing away of or damage to the vascular endothelial lining of the
organ. Thus, organ perfusion in this system can be performed, e.g., with
either hydrostatic perfusion (gravity or pressure fed flow) or
peristaltic perfusion by introducing flow to the organ from a peristaltic
(roller) pump.

[0098] A bubble detection system may be installed to sense bubbles in the
perfusate. An air sensor and sensor board are preferably used. The output
of the sensor activates a debubbler system, such as an open solenoid
valve, to rid bubbles from the perfusate flow prior to organ
introduction. As with all of the sensors and detectors in this system,
the bubble detector may be positioned at any point in the system that is
effective based on the particular parameters or design characteristics of
the system. For example, a bubble detector and debubbler system BD may be
positioned between the cam valve 205 and pressure sensor P1, as shown in
FIG. 1.

[0099] A stepping motor/cam valve 205, or other suitable variable valve
such as a rotary screw valve, may be arranged on the tubing 50c to
provide pulsatile delivery of the medical fluid to the organ 60, to
decrease the pressure of the medical fluid fed into the organ 60, and/or
to stop flow of medical fluid into the organ 60 if the perfusion pressure
exceeds a predetermined amount. Alternatively, a flow diverter or shunt
line may be provided in the perfusion apparatus to which the fluid flow
is diverted in the occurrence of a fault, such as excess pressure, for
example by opening and closing a valve or a series of valves. Specific
embodiments of the stepping motor/cam valve are shown in FIGS. 13A-13B
and 14A-14F. FIGS. 13A-13B show a stepping motor/rotational type cam
valve.

[0100]FIG. 13A is a top view of the apparatus. Tubing, for example,
tubing 50c, is interposed between a support 203 and cam 200. Cam 200 is
connected by a rod 201 to stepping motor 202. FIG. 13B is a side view of
the apparatus. The dashed line shows the rotational span of the cam 200.
In FIG. 13B, the cam 200 is in its non-occluding position. Rotated 180
degrees, the cam 200 totally occludes the tubing 50c with varying degrees
of occlusion therebetween. This stepping motor/cam valve is relatively
fast, for example, with respect to the embodiment shown in FIGS. 14A-14F;
however, it requires a strong stepping motor.

[0101] FIGS. 14A-14F disclose another stepping motor/cam valve 210
according to the invention. FIG. 14A is a side view of the apparatus
while FIG. 14c is a top view. Tubing, for example, tubing 50c, is
interposed between cam 220 and support 223. The cam 220 is connected to
stepping motor 222 by supports 221a-221d and helical screw 225, which is
connected to the stepping motor 222 via plate 222a. FIG. 14B shows the
supports 221a and plate 222a in front view. As shown in FIG. 14D, where
the support 221d is to the left of the center of the helical screw 225,
the tubing 50c is not occluded. However, as the helical screw 225 is
turned by the stepping motor 222, the support 221d moves to the left
(with respect to FIGS. 14D-14F) toward a position where the cam 220
partially or fully occludes the tubing 50c. Such apparatus is slower than
the apparatus of FIGS. 13A-13B, but is more energy efficient.

[0102] Medical fluid expelled from the organ 60 which has collected in the
bottom of the bag 69 (the cassette 65 or the organ chamber 40) is either
pumped out through tubing 81 by a pump 80 for filtration, passing through
a filter unit 82 and being returned to the organ bath, or is pumped out
by a pump 90 for circulation through tubing 91. The pumps 80, 90 are
preferably conventional roller pumps or peristaltic pumps; however, other
types of pumps may also be appropriate.

[0103] FIG. 25 shows a simplified schematic of a pump and pulse controller
2500 and the interaction of the pump and pulse controller with a
perfusion apparatus, such as shown in FIG. 1. Pump and pulse controller
2500 receives pressure sensor data input 2510 from pressure sensor P and
tachometer data input 2520. A tachometer may be used to set the phase
angle of the active wave. Pump and pulse controller 2500 converts this
information to motor drive output 2530, which powers pump 2540. FIG. 25A
shows various modes of operation that pump and pulse controller 2500 can
provide and how pump and pulse controller 2500 eliminates pressure pulse
waves from the perfusate flow and how it modulates perfusate flow rate
while maintaining a constant pressure pulse rate.

[0104] A peristaltic pump driven at a constant speed provides a constant
pressure wave in the associated tubing. FIG. 25A shows in the first mode
of operation the waveforms that result from a constant drive speed
applied to a peristaltic pump. The second mode of operation, called
active continuous, shows how the pressure pulse wave can be eliminated or
canceled out by applying a motor drive wave that is opposite to the
pressure wave of the pump. In the third mode of operation, called active
waveform amplitude modulating, the pump pressure pulse wave is canceled
by the motor drive wave, and a selected wave is added with a new
amplitude as compared to the original pressure pulse wave amplitude. In
the fourth mode of operation, called active waveform pulse width
modulating, the pump pressure pulse wave is canceled by the motor drive
wave, and a selected wave is added with a new pulse width as compared to
the original pressure pulse wave width. In an alternative mode of
operation, the frequency may be modulated by adding a new frequency wave
to the canceled waves.

[0105] A level sensor L2 in communication with the microprocessor 150 (see
FIG. 3) ensures that a predetermined level of effluent medical fluid is
maintained within the organ chamber 40. As shown in FIG. 2, a temperature
sensor T1 disposed in the tubing 91 relays the temperature of the medical
fluid pumped out of the organ bath along tubing 91 to the microprocessor
150, which monitors the same. A pressure sensor P2 disposed along the
tubing 91 relays the pressure therein to the microprocessor 150, which
shuts down the system if the fluid pressure in the tubing 91 exceeds a
predetermined limit, or activates an alarm to notify the operator that
the system should be shut down, for example, to clean filters or the
like.

[0106] As the medical fluid is pumped along tubing 91 it preferably passes
through a filter unit 95 (e.g., 25μ, 8μ, 2μ, 0.8μ, 0.2μ
and/or 0.1μ filters); a CO2 scrubber/O2 membrane 100 and an
oxygenator 110, for example, a JOSTRAT® oxygenator. The CO2
scrubber/O2 membrane 100 is preferably a hydrophobic macroporous
membrane with a hydrophilic (e.g., Hypol) coating in an enclosure. A
vacuum source (not shown) is utilized to apply a low vacuum on a side
opposite the hydrophilic coating by the activation of valve VV1. A
hydrostatic pressure of approximately 100 mm Hg is preferred for aqueous
passage through the membrane. The mechanical relief valve (not shown)
prevents the pressure differential from attaining this level. Immobilized
pegolated carbonic anhydrase may be included in the hydrophilic coating.
This allows bicarbonate to be converted to CO2 and subsequently
removed by vacuum venting. However, with organs such as kidneys which
have the ability to eliminate bicarbonate, this may be unnecessary except
in certain cases.

[0107] The oxygenator 110 is preferably a two stage oxygenator which
preferably includes a hydrophilically coated low porosity oxygen
permeable membrane. A portion of the medical fluid is diverted around the
oxygenator along tubing 111 in which is disposed a viability sensor V1,
which senses fluid characteristics, such as organ resistance
(pressure/flow), pH, pO2, pCO2, LDH, T/GST, Tprotein, lactate,
glucose, base excess and ionized calcium levels indicative of an organ's
viability. The viability sensor V1 is in communication with the
microprocessor 150 and allows the organ's viability to be assessed either
automatically or manually. One of two gases, preferably 100% oxygen and
95/5% oxygen/carbon dioxide, is placed on the opposite side of the
membrane depending on the pH level of the diverted medical fluid.
Alternatively, another pump (not shown) may be provided which pumps
effluent medical fluid out of the organ chamber 40 and through a
viability sensor before returning it to the bath, or the viability sensor
can be placed on tubing 81 utilizing pump 80. In embodiments, the fluid
characteristics may be analyzed in a separate diagnostic apparatus and/or
analyzer as shown in FIGS. 28-31.

[0108] The sensed fluid characteristics, such as organ resistance
(pressure/flow), pH, pO2, pCO2, LDH, T/GST, Tprotein, lactate,
glucose, base excess and ionized calcium levels may be used to analyze
and determine an organ's viability. The characteristics may be analyzed
individually or multiple characteristics may be analyzed to determine the
effect of various factors. The characteristics may be measured by
capturing the venous outflow of the organ and comparing its chemistry to
the perfusate inflow. The venous outflow may be captured directly and
measured or the organ bath may be measured to provide a rough
approximation of the fluid characteristics for comparisons over a period
of time.

[0109] In embodiments, an organ viability index is provided taking into
account the various measured factors identified above, such as vascular
resistance, pH, etc. The index may be organ specific, or may be adaptable
to various organs. The index compiles the monitored parameters into a
diagnostic summary to be used for making organ therapy decisions and
deciding whether to transplant the organ. The index may be automatically
generated and provided to the physician. The index is preferably computer
generated via a connection to the perfusion apparatus, transporter,
cassette and/or organ diagnostic apparatus. The additional information,
such as donor specific information, may be entered into a single computer
at the site of the perfusion apparatus, transporter, Cassette and/or
organ diagnostic apparatus or may be entered in a remote computer and
linked to the perfusion apparatus, etc. In embodiments, the index may be
made available over a computer network such as a local area network or
the Internet for quick comparison, remote analysis and data storage.

[0110] The organ viability index provides measurements and normal ranges
for each characteristic, such as vascular resistance and perfusate
chemistry characteristics based on pH, pO2, pCO2, LDH, T/GST,
Tprotein, lactate, glucose, base excess and ionized calcium levels. For
example, at approximately 5° C., normal pH may be from 7.00 and
8.00, preferably, from 7.25 and 7.75 and more preferably from 7.50 and
7.60 and base excess may be in the range of from -10 to -40, preferably
from -15 to -30, and more preferably from -20 to -25. Measurements that
are outside the normal range may be indicated visually, e.g., by an
asterisk or other suitable notation, aurally or by machine perceivable
signals. The characteristics give the physician insight into the
metabolism of the organ, such as stability of the metabolism, consumption
of glucose, creation of lactic, acid and oxygen consumption.

[0111] The index may also provide identifying information, such as age,
gender, blood type of the donor and any expanded criteria; organ
information, such as organ collection date and time, warm ischemia time,
cold ischemia time and vascular resistance; apparatus information, such
as flow rate, elapsed time the pump has been operating and pressure; and
other identifiers such as UNOS number and physician(s) in charge. The
index may additionally provide temperature corrections if desired.

[0112] Returning to FIG. 2 and the flow and/or treatment of the medical
fluid or perfusate in perfusion apparatus 1, alternative to the pump 90,
filter unit 95, the CO2 scrubber/O2 membrane 100 and/or the
oxygenator 110, a modular combined pump, filtration, oxygenation and/or
debubbler apparatus may be employed such as that described in detail in
simultaneously filed co-pending U.S. patent application Ser. No.
09/039,318, which is hereby incorporated by reference. As shown in FIGS.
4-10, the apparatus 5001 is formed of stackable modules. The apparatus
5001 is capable of pumping a fluid through a system as well as
oxygenating, filtering and/or debubbling the fluid. The modules are each
formed of a plurality of stackable support members and are easily
combinable to form a compact apparatus containing desired components.
Filtration, oxygenation and/or degassing membranes are disposed between
the support members.

[0113] FIGS. 4-8 show various modules that may be stacked to form a
combined pump, filtration, oxygenation and/or debubbler apparatus, such
as the combined pump, filtration, oxygenation and debubbler apparatus
5001 shown in FIGS. 9-10. As depicted in these figures, the combined
pump, filtration, oxygenation and debubbler apparatus 5001 is preferably
formed of a plurality of stackable support members groupable to form one
or more modules.

[0114] Interposed between the plurality of stackable support member are
filtration, oxygenation and/or degassing membranes depending on a
particular user's needs. The filtration, oxygenation and/or degassing
membranes are preferably commercially available macro-reticular
hydrophobic polymer membranes hydrophilically grafted in a commercially
known way, such as, for example, ethoxylation, to prevent protein
deprivation, enhance biocompatibility with, for example, blood and to
reduce clotting tendencies. The filtration membrane(s) is preferably
hydrophilically grafted all the way through and preferably has a porosity
(pore size) within a range of 15 to 3μ, more preferably 20 to 30μ,
to filter debris in a fluid, preferably without filtering out cellular or
molecular components of the fluid. The degassing membrane(s) and
oxygenation membrane(s) are hydrophilically surface treated to maintain a
liquid-gas boundary. The degassing membrane(s) and oxygenation
membrane(s) preferably have a porosity of 15μ or less, more preferably
10μ or less.

[0115] The modules may include a first pump module 5010, as shown in
exploded view in FIG. 4; a filtration module 5020, as shown in exploded
view in FIG. 5; an oxygenation module 5030, as shown in exploded view in
FIG. 6; a debubbler module 5040, as shown in exploded view in FIG. 7; and
a second pump module 5050, as shown in exploded view in FIG. 8. The pump
modules are each connected to a source of pump fluid and are actuated
either manually or by the microprocessor. The support members are
preferably similarly shaped. For example, the support members may each be
plate-shaped; however, other shapes may also be appropriate. As shown in
FIG. 10, the support members are preferably removably connected by screws
or bolts 5065; however, other fasteners for assembling the apparatus may
also be appropriate.

[0116] The first pump module 5010 preferably includes a first (end)
support member 5011, a second support member 5012 with a cut-out center
area 5012c, a diaphragm 5013 and a third support member 5014. The support
members of this module and each of the other modules are preferably thin
and substantially flat (plate-like), and can be formed of any appropriate
material with adequate rigidity and preferably also biocompatibility. For
example, various resins and metals may be acceptable. A preferred
material is an acrylic/polycarbonate resin.

[0117] The first (end) support member 5011 is preferably solid and
provides support for the pump module 5010. The first (end) support member
5011 preferably includes a domed-out cavity for receiving pump fluid such
as air. Tubing 5011t is provided to allow the pump fluid to enter the
pump module 5010. The diaphragm 5013 may be made of any suitable elastic
and preferably biocompatible material, and is preferably polyurethane.
The third support member 5014 includes a domed-out fluid cavity 5014d and
tubing 5014t for receiving fluid, such as, for example, blood or an
artificial perfusate, into the cavity 5014d of the pump module 5010. The
first pump module, or any of the other modules, may also include a port
5014p for sensors or the like. Preferably hemocompatible anti-backflow
valves serve to allow unidirectional flow through the pump module 5010.

[0118] The filtration module 5020 preferably includes a filtration
membrane 5021m which forms a boundary of cavity 5014d, a first support
member 5022 with a cut-out center area 5022c, a degassing membrane 5022m
and second and third support members 5023 and 5024. The filtration
membrane 5021m is preferably a 25μ macro-reticular filtration membrane
modified to enhance biocompatibility with, for example, blood and to
reduce clotting tendencies (like the other supports, filters and
membranes in the device). The degassing membrane 5022m is preferably a
0.2-3μ macro-reticular degassing membrane with a reverse flow aqueous
pressure differential of at least 100 mmHg for CO2 removal surface
modified to enhance biocompatibility.

[0119] The first support 5022 includes tubing 5022t for forwarding fluid
into the oxygenation module 30, or another adjacent Module, if
applicable, after it has passed through the filtration membrane 5021m and
along the degassing membrane 5022m. The second support member 5023 of the
filtration module 5020 includes a domed-out fluid cavity 5023d and tubing
5023t through which a vacuum may be applied to the cavity 5023d to draw
gas out of the fluid through degassing membrane 5022m. The fourth support
member 5024 is preferably solid and provides support for the filtration
module 5020. The third support member can also include tubing 5024t
through which a vacuum may be applied to draw gas out of the fluid
through the degassing, membrane 5031m of the oxygenation module 5030 as
discussed below. The filtration module 5020, or any of the other modules,
may also include a port 5023p for sensors or the like.

[0120] The oxygenation module 5030 includes a degassing membrane 5031m, a
first support member 5032, a filtration membrane 5033m, an oxygenation
membrane 5034m, a second support member 5034 with a cut-out center area
5034c, and third and fourth support members 5035, 5036. The degassing
membrane 5031m is preferably a 0.2-3μ macro-reticular degassing
membrane with a reverse flow aqueous pressure differential of at least
100 mmHg surface modified to enhance biocompatibility.

[0121] The first support member 5032 includes a domed-out fluid cavity
5032d. The surface of the domed-out fluid cavity 5032d preferably forms a
tortuous path for the fluid, which enhances the oxygenation and degassing
of the fluid. The filtration membrane 5033m is preferably a 25μ
macro-reticular filtration membrane modified to enhance biocompatibility.
The oxygenation membrane 5034m is preferably a 0.2-1μ macro-reticular
oxygenation membrane with a reverse flow aqueous pressure differential of
at least 100 mmHg surface modified to enhance biocompatibility.

[0122] The second support member 5034 includes tubing 5034t for forwarding
fluid out of the oxygenation module 5030 into the debubbler module 5040,
or another adjacent module, if applicable. The third support member 5035
includes adorned-out cavity 5035d and tubing 5035t for receiving oxygen
from an external source. The fourth support member 5036 is preferably
solid and provides support for the oxygenation module 5030.

[0123] The debubbler module 5040 includes a first support member 5041, a
filtration membrane 5042m, a degassing membrane 5043m, a second support
member 5043 having a cut-out center area 5043c, and a third support
member 5044. The first support member 5041 has a domed-out fluid cavity
5041d.

[0124] The filtration membrane 5042m is preferably a 25μ
macro-reticular filtration membrane modified to enhance biocompatibility.
The degassing membrane 5043m is preferably a 0.2-3μ macro-reticular
degassing membrane with a reverse flow aqueous pressure differential of
at least 100 mmHg surface modified to enhance biocompatibility. The
second support member 5043 has tubing 5043t for forwarding fluid out of
the debubbler module 5040 into the pump module 5050, or another adjacent
module, if applicable. The third support member 5044 includes a domed-out
cavity 5044d and tubing 5044t through which a vacuum may be applied to
draw gas out of the fluid through the degassing membrane 5043m.

[0125] The second pump module 5050 may correspond to the first pump module
5010. It preferably includes a first support member 5051, a diaphragm
5052, a second support member 5053 with a cut-out center area 5053c, and
a third (end) support member 5054. The first support member 5051 includes
a domed out fluid cavity 5051d and tubing 5051t for allowing fluid to
exit the pump module. The diaphragm 5052 is preferably a polyurethane
bladder.

[0126] The third (end) support piece member 5054 is preferably solid and
provides support for the pump module 5050. Support member 5054 preferably
includes a domed out cavity (not shown) for receiving pump fluid. Tubing
5054a is provided to allow the pump fluid such as air to enter the pump
module 5050. Preferably hemocompatible anti-backflow valves may serve to
allow unidirectional flow through the pump module 5050.

[0127] In operation, blood and/or medical fluid enters the first pump
module 5010 through tube 5014t passes through the filtration membrane
5021m and along the degassing membrane 5022m. A small vacuum is applied
through tubing 5023t to draw gas through the degassing membrane 5022m.
Next, the blood and/or medical fluid travels into the oxygenation module
5030 via internal tubing 5022t, passing along the degassing membrane
5031m, through the filtration membrane 5033m and along the oxygenation
membrane 5034m. Oxygen is received into the domed-out cavity 5035d of the
third support member of the oxygenation module 5030 via tubing 5035t and
passes through the oxygenation membrane 5034m into the blood and/or
medical fluid as the blood and/or medical fluid travels along its
surface.

[0128] After being oxygenated by the oxygenation module 5030, the blood
and/or medical fluid then travels via internal tubing 5034t into the
debubbler module 5040. The blood and/or medical fluid passes through the
filtration membrane 5042m and along the degassing membrane 5043m. A small
vacuum force is applied through tubing 5044t to draw gas out of the blood
and/or medical fluid through the degassing membrane 5043m. After passing
through the degassing module 5040, the blood and/or medical fluid travels
into the second pump module 5050 through tubing 5041t, and exits the
second pump module 5050 via tubing 5051t.

[0129] After passing through the oxygenator 110, or alternatively through
the combined pump, oxygenation, filtration and/or degassing apparatus
5001, the recirculated medical fluid is selectively either directed to
the reservoir 15a or 15b not in use along tubing 92a or 92b,
respectively, by activating the respective valve LV2 and LV5 on
the tubing 92a or 92b, or into the organ chamber 40 to supplement the
organ bath by activating valve LV1. Pressure sensors P3 and P4
monitor the pressure of the medical fluid returned to the bag 15a or 15b
not in use. A mechanical safety valve MV2 is provided on tubing 91
to allow for emergency manual cut off of flow therethrough. Also, tubing
96 and manual valve MV1 are provided to allow the apparatus to be
drained after use and to operate under a single pass mode in which
perfusate exiting the organ is directed to waste rather than being
recirculated (recirculation mode.)

[0130] A bicarbonate reservoir 130, syringe pump 131 and tubing 132, and
an excretion withdrawal unit 120, in communication with a vacuum (not
shown) via vacuum valve VV2, and tubing 121a, 122a are also each
provided adjacent to and in communication with the organ chamber 40.

[0131] The present invention also provides for perfusion apparatus adapted
for organs with complex vasculature structures, such as the liver. Using
the liver as an example, FIG. 26 shows perfusion apparatus 2600.
Perfusion apparatus 2600 has a single pump 2610, which is preferably a
roller pump or peristaltic pump. The tubing splits into two or more
directions with, for example, three tubes going toward the portal vein
side of the liver (portal tubing 2625) and one tube going toward the
hepatic artery side of the liver (hepatic tubing 2626). The portal side
of perfusion apparatus 2600 has more tubes because the portal side of the
liver uses three to ten times the flow that the hepatic side uses. FIG.
27 shows a perspective view of pump 2610 and the tubing split into portal
tubing 2625 and hepatic tubing 2626.

[0132] Both the portal side and the hepatic side of perfusion apparatus
2600 preferably have a filter 2630, bubble trap 2640, pressure transducer
2650, temperature transducer 2660, and flow sensor 2670. An additional
temperature transducer 2660 may be present in fluid return tubing 2620.
The organ may be cooled as discussed above, for example by an ice and
water bath 2680 or by a cryogenic fluid. In embodiments using cryogenic
fluids, the design should be such that organ freezing is prevented.

[0133] Multiple pumps may be used; however, utilizing multiple pumps
generally increases the size and cost of the apparatus. Utilizing a
single pump 2610 for both vasculature systems provides a variety of modes
that can be used to perfuse a liver. After each bubble trap 2640, the
tubing splits into two directions. On the hepatic side, hepatic infusion
valve 2685 controls the flow to the hepatic side of the liver and hepatic
wash valve 2686 controls the flow into the organ bath. On the portal
side, portal infusion valve 2695 controls the flow to the portal Side of
the liver and portal wash valve 2696 controls the flow into the organ
bath. Preferably, each pair of infusion valves and wash valves operates
in an on/off or either/or manner. In other words, when, for example, the
portal side is set to infuse, the portal wash valve 2696 is closed. The
following table shows various modes of operation for perfusion apparatus
2600.

[0134] The modes of operation identified in the table above show options
for infusing a liver. In the first mode, Portal Only, the portal side of
the liver is infused. Therefore, the portal valves are set to infuse,
which means that portal infusion valve 2695 is open and portal wash valve
2696 is closed. Also, in a Portal Only mode, hepatic infusion valve 2685
is closed and hepatic wash valve 2686 is open. In a Portal Only mode, the
portal pressure is dominant, which means the pressure is controlled by
the pressure transducer 2650 on the portal side. In this mode, there is
no hepatic infusion.

[0135] In a Portal Priority mode, the portal valves and the hepatic valves
are set to infuse. The portal pressure is dominant; and therefore, the
hepatic side is a slave to the portal side. In an Alternating mode, the
portal valves are set to infuse and the hepatic valves switch between an
infuse setting and a wash setting. In an Alternating mode, when the
hepatic valves are set to infuse, the hepatic side provides the dominant
pressure. When the hepatic valves are set to wash, the portal side
provides the dominant pressure. This type of alternating pressure control
provides the portal side with a wavy flow and provides the hepatic side
with a pulsed flow.

[0136] The present invention also provides an organ diagnostic system 2800
shown in FIG. 28. Organ diagnostic system 2800 has a computer 2810 and an
analyzer 2820. Connected to both computer 2810 and analyzer 2820 is an
organ evaluation instrument 2830, also shown in FIG. 29. Organ diagnostic
system 2800 is preferably provided with suitable displays to show the
status of the system and the organ. Organ evaluation instrument 2830 has
a perfusate chamber 2840 and an organ chamber 2850. Connecting analyzer
2820 and organ evaluation instrument 2830 is a transfer line 2860. Organ
diagnostic system 2800 provides analysis of an organ and produces an
organ viability index quickly and in a sterile cassette, preferably
transferable from perfusion apparatus 1 and/or transporter 1900. The
organ viability index is preferably produced by flow and temperature
programmed single-pass perfusion and in-line automatic analysis. The
analysis may be performed in a multi-pass system, although a beneficial
aspect of the single-pass system is that it can be configured with a
limited number of sensors and requires only enough perfusate to perform
the analysis. Single-pass perfusion also allows for an organ inflow with
a perfusate having a known and predetermined chemistry. This increases
the flexibility of types and contents of perfusates that may be
delivered, which can be tailored and modified to the particular analysis
in process.

[0137]FIG. 29 shows a perspective view of organ evaluation instrument
2830. Organ evaluation instrument 2830 has a perfusate chamber 2840 and
an organ chamber 2850. Organ chamber 2850 may be insulated and preferably
has a lid 2910 that may be removable or may be hinged. Organ chamber 2850
is preferably configured to receive cassette 65, preferably without
opening cassette 65 or jeopardizing the sterility of the interior of
cassette 65. Cassette 65 and organ chamber 2850 are preferably
constructed to fit or mate such that efficient heat transfer is enabled.
The geometric elements of cassette 65 and organ chamber 2850 are
preferably constructed such that when cassette 65 is placed within organ
chamber 2850, the elements are secure for analysis. A port 2920 is also
provided to connect transfer line 2860.

[0138] FIG. 30 shows a single-pass fluid system of organ diagnostic system
2800. The initial perfusion fluids 3000 are contained in a chamber 3010.
Chamber 3010 is preferably temperature controlled by a heating and
cooling system. Fluid flow within the system is monitored by flow sensor
3020 and controlled by signaling to pinch valves 3030 and pumps 3040. The
fluid system also provides a bubble trap 3050, a pressure transducer 3060
and a temperature transducer 3070. Heat exchanger 3080 provides
temperature control and heating and cooling to the fluid within the
system prior to organ perfusion. The organ is perfused in cassette 65.
The fluid in the organ bath may be collected, or the venous outflow may
be captured, to be analyzed. The fluid is collected and passed via
transfer line 2860 to analyzer 2820. Transfer line 2860 may also be
provided with a separate heating and cooling unit. After the fluid is
analyzed, it may be collected in a waste receptacle 3090.

[0139] FIG. 31 shows a logic circuit for organ diagnostic system 2800. The
computer provides control parameters and receives results and data from
the analyzer. The logic circuit shows inputs from the sensors to the
microcontroller and outputs to hardware elements, such as perfusate
coolers, perfusate heaters, pinch valves, pumps, transferline
heater/cooler and displays.

[0140] The method according to the invention preferably utilizes apparatus
such as that discussed above to perfuse an organ to sustain, monitor
and/or restore the viability of an organ and/or to transport and/or store
the organ. Preservation of the viability of an organ is a key factor to a
successful organ transplant. Organs for transplant are often deprived of
oxygen (known as ischemia) for extended periods of time due to disease or
injury to the donor body, during removal of the organ from the donor body
and/or during storage and/or transport to a donee body. The perfusion,
diagnostic, and/or transporter apparatus of the present invention have
the ability to detect the cell chemistry of an organ to be transplanted
in order to adjust the perfusate and control the cellular metabolism to
repair ischemic damage to the organ and to prevent reperfusion injury.
One specific outcome of ischemic injury may be apoptosis or programmed
cell death. Specific agents and additives provided to an organ by the
perfusion, diagnostic and/or transporter apparatus, under conditions
controlled by the particular apparatus, may interrupt, decrease and/or
reverse apoptosis.

[0141] In preferred methods of the present invention, an organ or tissue
is treated ex vivo by mechanical, physical, chemical or genetic
manipulation and/or modification to treat disease and/or treat damage to
and/or enhance the properties of the organ or tissue. An organ or tissue
sample may be removed from a first body, modified, treated and/or
analyzed outside the first body and either returned to the first body or
transplanted to a second body. An advantage of the apparatus is that it
enlarges the time that an organ may be available for ex vivo treatment,
e.g., for hours (e.g. 2; 4, 6, 8, 10, 12 or more hours) or even days
(e.g. 2, 4, 6, 8, 10, 12 or more days) or weeks (e.g. 1, 2, 3, 4, 5, 6,
7, 8 or more weeks). In preferred embodiments, the perfusion, diagnostic
and/or transporter apparatus of the present invention may be used to
provide particular solutions or chemicals to an organ or tissue or may be
used to perform particular treatments including flushing or washing an
organ or tissue with particular solutions or chemicals. Ex vivo
treatments may be performed on tissue or an organ to be transplanted or
may be performed on tissue or an organ that has been removed from a
patient and is to be returned to the patient after the desired procedure
is performed. Ex vivo treatments include but are not limited to treatment
of tissue or an organ that has endured a period or periods of ischemia
and/or apoxia. Ex vivo treatments may involve performing surgical
techniques on an organ, such as cutting and suturing an organ, for
example to remove necrotic tissue. Any surgical or other treatment
technique that may be performed on tissue or an organ in vivo may also be
performed on tissue or an organ ex vivo. The benefit of such ex vivo
treatment may be seen, for example, in, the application of radiation or
chemotherapy to treat a tumor present in or on an organ, to prevent other
portions of the patient from being subjected to extraneous radiation or
chemotherapy during treatment. The perfusion and transporter apparatus of
the present invention also provide additional time for a physician to
maintain the tissue or organ before, during and/or after performing a
particular technique on the tissue or organ.

[0142] Particles trapped in an organ's vasculature may prevent the organ
from perfusing properly, or may cause the organ to function improperly,
before and/or after transplantation. Perfusion, diagnostic and
transporter apparatus of the invention provide ex vivo techniques include
perfusing, flushing or washing an organ with suitable amounts of a
thrombolytic agent, such as streptokinase, to dissolve blood clots that
have formed or to prevent the formation of blood clots in an organ and to
open the vasculature of the organ. Such techniques are disclosed, for
example, in U.S. Provisional Patent Application ______, filed Aug. 25,
2000, Attorney Docket No. 106996, the entire disclosure of which is
hereby incorporated by reference.

[0143] Another concern with organ transplantation is the degree to which a
recipient may be medicated to prevent organ rejection. In organ
transplantation, a further ex vivo technique involves modifying the organ
to avoid having it activate the immune system of the donee to prevent or
reduce organ rejection and to limit or prevent the need to suppress the
donee's immune system before, during and/or after organ transplantation
so as to increase the tolerance of the donee to the transplanted organ.
Modifications of an organ may, for example, encourage the donee body to
recognize the transplanted organ as autologous. The perfusion, diagnostic
and/or transporter apparatus of the present invention may deliver
substances such as chemical compounds, natural or modified antibodies,
immunotoxins or the like, to an organ and may assist the organ to adsorb,
absorb or metabolize such substances to increase the likelihood that the
organ will not be rejected. These substances may also mask the organ by
blocking, killing, depleting and/or preventing the maturation of
allostimulatory cells (dendritic cells, passenger leukocytes, antigen
presenting cells, etc.) so that the recipient's immune system does not
recognize it or otherwise recognizes the organ as autologous. An organ
may be treated just prior to transplantation or may be pretreated hours,
days or weeks before transplantation. Such techniques are further
described in U.S. Provisional Patent Application No. ______, filed Aug.
25, 2000, Attorney Docket No. 100034, the entire disclosure of which is
hereby incorporated by reference.

[0144] Substances, such as modified or unmodified immunoglobulin, steroids
and/or a solution containing polyethylene glycol (PEG) and an antioxidant
such as glutathione, may also be provided to an organ or tissue to mask
the organ or to treat the onset of intimal hyperplasia during
cryopreservation and/or organ or tissue transplantation. These solutions
may be provided to an organ or tissue by perfusion, diagnostic and/or
transporter apparatus of the invention. Exemplary such solutions and
methods are disclosed in U.S. patent application Ser. No. 09/499,520, the
entire disclosure of which is hereby incorporated by reference.

[0145] The perfusion, diagnostic and transporter apparatus of the
invention may be used in conjunction with the above techniques and
methods and/or in conjunction with further techniques and methods, to
perform research on an organ or tissue. The various apparatus may enlarge
the time that an organ may be available for ex vivo treatment, e.g., for
hours (e.g. 2, 4, 6, 8, 10, 12 or more hours) or even days (e.g. 2, 4, 6,
8, 10, 12 or more days) or weeks (e.g. 1, 2, 3, 4, 5, 6, 7, 8 or more
weeks). During the period in which the organ is preserved and/or
maintained, various drug research and development may be performed on
and/or with the organ. Further treatments may be performed for research
purposes, such as developing immunomodification parameters. Since the
organ or tissue may be maintained and/or analyzed at or near physiologic
parameters, an organ may be tested for the effects of various treatments
and/or substances on the organ or tissue ex vivo. The perfusion,
diagnostic and/or transporter apparatus may be used to perfuse blood or a
synthetic blood substitute through an organ while monitoring the organ
and the organ outflow to analyze the condition of the organ and/or to
determine the effect on it of the various treatments.

[0146] Preferred methods according to the present invention focus on three
concepts in order to preserve an organ's viability prior to transplant of
the organ into a donee body--treating the cellular mitochondria to
maintain and/or restore pre-ischemia energy and enzyme levels, preventing
general tissue damage to the organ, and preventing the washing, away of
or damage to the vascular endothelial lining of the organ.

[0147] The mitochondria are the energy source in cells. They need large
amounts of oxygen to function. When deprived of oxygen, their capacity to
produce energy is reduced or inhibited. Additionally, at temperatures
below 20° C. the mitochondria are unable to utilize oxygen to
produce energy. By perfusing the organ with an oxygen rich medical fluid
at normothermic temperatures, the mitochondria are provided with
sufficient amounts of oxygen so that pre-ischemia levels of reserve high
energy nucleotide, that is, ATP levels, in the organ reduced by the lack
of oxygen are maintained and/or restored along with levels of enzymes
that protect the organ's cells from free radical scavengers. Pyruvate
rich solutions, such as that disclosed in U.S. Pat. No. 5,066,578, are
incapable of maintaining and/or restoring an organ's pre-ischemia energy
levels and only function in the short term to raise the level of ATP a
small, amount. That is, organs naturally have significant pyruvate
levels. Providing an organ with additional pyruvate will not assist in
restoring and/or maintaining the organ's pre-ischemia energy levels if
the mitochondria are not provided with sufficient oxygen to produce
energy. Thus, the normothermic perfusion fluid may contain pyruvate but
may also contain little or no pyruvate. For example, it can contain less
than 6 mM of pyruvate, 5 mM, 4 mM, or even no pyruvate. Other known
preservation solutions, such as that disclosed in U.S. Pat. No.
5,599,659, also fail to contain sufficient oxygen to restore and/or
maintain pre-ischemia energy and enzyme levels.

[0148] After maintaining and/or restoring the organ's pre-ischemia energy
levels by perfusing the organ with an oxygen rich first medical fluid at
normothermic or near-normothermic temperatures (the normothermic mode),
the organ is perfused with a second medical fluid at hypothermic
temperatures (the hypothermic mode). The hypothermic temperatures slow
the organ's metabolism and conserve energy during storage and/or
transport of the organ prior to introduction of the organ into a donee
body. The medical fluid utilized in the hypothermic mode contains little
or no oxygen, which cannot be utilized by mitochondria to produce energy
below approximately 20° C. The medical fluid may include
antioxidants and other tissue protecting agents, such as, for example,
ascorbic acid, glutathione, water soluble vitamin E, catalase, or
superoxide dismutase to protect against high free radical formation which
occurs at low temperatures due to the reduction in catalase/superoxide
dismutase production. Further, various drugs and agents such as hormones,
vitamins, nutrients, antibiotics and others may be added to either
solution where appropriate. Additionally, vasodilators, such as, for
example, peptides, may be added to the medical fluid to maintain flow
even in condition of injury.

[0149] Prior to any normothermic perfusion with the oxygen rich first
medical fluid at normothermic temperatures, the organ may be flushed with
a medical solution containing little or no oxygen and preferably
containing antioxidants. The flushing is usually performed at hypothermic
temperatures but can, if desired and/or as necessary, be performed at
normothermic or near-normothermic temperatures. Flushing can be followed
by one or more of hypothermic perfusion, normothermic perfusion, and/or
static storage, in any necessary and/or desired order. In some cases,
normothermic perfusion may not be necessary.

[0150] The normothermic perfusion, with or without prior hypothermic
flushing, may also be performed on an organ that has already been
subjected to hypothermic temperatures under static or perfusion
conditions, as well as on normothermic organs.

[0151] The organ may be perfused at normothermic or near-normothermic
temperatures to sustain, monitor and/or restore its viability prior
and/or subsequent to being perfused at hypothermic temperatures for
storage and then may be transported without or preferably with
hypothermic perfusion. Also, the normothermic perfusion may be performed
in vivo prior to removal of the organ from the donor body. Further, the
organ may be perfused at normothermic temperatures to sustain, monitor
and/or restore its viability prior to being perfused at hypothermic
temperatures preparatory to storage and/or transport. Then the organ may
be transplanted into a donee body while remaining at hypothermic
temperatures, or it may first be subjected to normothermic perfusion to
help it recover from the effects of storage and/or transport. In the
latter case, it may then be transplanted at normothermic temperatures, or
preferably, be hypothermically perfused again for transplantation at
hypothermic temperatures. After transplant, the organ may optionally
again be perfused at normothermic temperatures in vivo, or allowed to
warm up from the circulation of the donee.

[0152] By way of Example only, and without being limited thereto, FIG. 16
shows an exemplary diagram of possible processing steps according to the
invention. The Figure shows various possible processing steps of multiple
organ recovery (MOR) from organ explant from the organ donor through
implant in the donee, including possible WIT (warm ischemia time) and
hypoxia damage assessment. Several exemplary scenarios are set forth in
the following discussion.

[0153] For example, in one embodiment of the present invention, the organ
can be harvested from the donor under beating heart conditions. Following
harvesting, the organ can be flushed, such as with any suitable solution
or material including, but not limited to VIASPAN (a preservation
solution available from DuPont), other crystalloid solution, dextran, HES
(hydroxyethyl starch), solutions described in U.S. patent application
Ser. No. 09/628,311, filed Jul. 28, 2000, the entire disclosure of which
is hereby incorporated by reference, or the like. The organ can then be
stored statically, for example, at ice temperatures (for example of from
about 1 to about 10° C.).

[0154] In another embodiment, such as where the organ has minimal WIT and
minimal vascular occlusion, a different procedure can be used. Here, the
organ can again be harvested under beating heart conditions, followed by
flushing, preferably at hypothermic temperatures. If necessary to
transport the organ, the organ can be stored in a suitable transporter
at, for example, ice temperatures. Flow to the organ can be controlled by
a set pressure maximum, where preset pressure minimum and pressure
maximum values control the pulse wave configuration. If necessary to
store the organ for a longer period of time, such as for greater than 24
hours, the organ can be placed in the MOR. In the MOR, a suitable
perfusate can be used, such as a crystalloid solution, dextran or the
like, and preferably at hypothermic temperatures. Preferably, the
hypothermic temperatures are from about 4 to about 10° C., but
higher or lower temperatures can be used, as desired and/or necessary.
Preferably, the perfusate solution contains specific markers to allow for
damage assessment, although damage assessment can also be made by other
known procedures. When desired, the organ can then be returned to the
transporter for transport to the implant site.

[0155] As a variation of the above procedure, an organ having minimal WIT
and minimal vascular occlusion can be harvested under non-beating heart
conditions. Here, the organ can flushed, preferably at hypothermic
temperatures and, if necessary, stored for transport in a suitable
transporter at, for example, ice temperatures. As above, flow to the
organ can be controlled by a set pressure maximum, where preset pressure
minimum and pressure maximum values control the pulse wave configuration.
The organ can be placed in the MOR, either for extended storage and/or
for damage assessment. In the MOR, a suitable perfusate can be used, such
as a crystalloid solution, dextran or the like, and preferably at
hypothermic temperatures. Preferably, the hypothermic temperatures are
from about 4 to about 10° C., but higher or lower temperatures can
be used, as desired and/or necessary. Preferably, the perfusate solution
contains specific markers to allow for damage assessment, although damage
assessment can also be made by other known procedures. Following
hypothermic perfusion, a second perfusion can be utilized, preferably at
normothermic temperatures. Any suitable perfusion solution can be used
for this process, including solutions that contain, as desired,
oxygenated media, nutrients, and/or growth factors. Preferably, the
normothermic temperatures are from about 12 to about 24° C., but
higher or lower temperatures can be used, as desired and/or necessary.
The normothermic perfusion can be conducted for any suitable period of
time, for example, for from about 1 hour to about 24 hours. Following
recovery from the normothermic perfusion, the organ is preferably
returned to a hypothermic profusion using, for example, a suitable
solution such as a crystalloid solution, dextran or the like, and
preferably at hypothermic temperatures. When desired, the organ can then
be returned to the transporter for transport to the implant site.

[0156] In embodiments where the organ has high WIT, and/or where there is
a high likelihood of or actual; vascular occlusion, variations on the
above processes can be used. For example, in the case where the organ is
harvested under non-beating heart conditions, the organ can be flushed as
described above. In addition, however, free radical scavengers can be
added to the flush solution, if desired. As above, the organ can be
stored for transport in a suitable transporter at, for example, ice
temperatures, where flow to the organ can be controlled by a set pressure
maximum, and where preset pressure minimum and pressure maximum values
control the pulse wave configuration. The organ can be placed in the MOR,
either for extended storage and/or for damage assessment. In the MOR, a
suitable perfusate can be used, such as a crystalloid solution, dextran
or the like, and preferably at hypothermic temperatures. Preferably, the
hypothermic temperatures are from about 4 to about 10° C., but
higher or lower temperatures can be used, as desired and/or necessary.
Preferably, the perfusate solution contains specific markers to allow for
damage assessment, although damage assessment can also be made by other
known procedures. Following hypothermic perfusion, a second perfusion can
be utilized, preferably at normothermic temperatures. Any suitable
perfusion solution can be used for this process, including solutions that
contain, as desired, oxygenated media, nutrients, and/or growth factors.
Preferably, the normothermic temperatures are from about 12 to about
24° C., but higher or lower temperatures can be used, as desired
and/or necessary. The normothermic perfusion can be conducted for any
suitable period of time, for example, for from about 1 hour to about 24
hours. If desired, and particularly in the event that vascular occlusion
is determined or assumed to be present, a further perfusion can be
conducted at higher normothermic temperatures, for example of from about
24 to about 37° C. This further perfusion can be conducted using a
suitable solution that contains a desired material to retard the vascular
occlusion. Such materials include, for example, clotbusters such as
streptokinase. Following recovery from the normothermic perfusion(s), the
organ is preferably returned to a hypothermic profusion using, for
example, a suitable solution such as a crystalloid solution, dextran or
the like, and preferably at hypothermic temperatures. When desired, the
organ can then be returned to the transporter for transport to the
implant site.

[0157] The organ cassette according to the present invention allows an
organ(s) to be easily transported to an organ recipient and/or between
organ perfusion, diagnostic and/or portable transporter apparatus, such
as, for example, transporter 1900 described above or a conventional
cooler or a portable container such as that disclosed in co-pending U.S.
application Ser. No. 09/161,919. Because the organ cassette may be
provided with openings to allow the insertion of tubing of an organ
perfusion, transporter or diagnostic apparatus into the cassette for
connection to an organ disposed therein, or may be provided with its own
tubing and connection device or devices to allow connection to tubing
from an organ perfusion, transporter or diagnostic apparatus and/or also
with its own valve, it provides a protective environment for an organ for
storage, analysis and/or transport while facilitating insertion of the
organ into and/or connection of an organ to the tubing of an organ
perfusion, transporter or diagnostic device. Further, the organ cassette
may also include a handle to facilitate transport of the cassette and may
be formed of a transparent material so the organ may be visually
monitored.

[0158] Optionally, transporter 1900 and/or cassette 65 may include a
Global Positioning System (GPS) (not shown) to allow tracking of the
location of the organ(s). The apparatus may also include a data logger
and/or transmitter (not shown) to allow monitoring of the organ(s) at the
location of the apparatus or at another location.

[0159] The method of the invention will be discussed below in terms of the
operation of the apparatus shown in FIG. 2. However, other apparatus may
be used to perform the inventive method.

[0160] As previously discussed, the apparatus discussed above can operate
in two modes: a normothermic perfusion mode and a hypothermic perfusion
mode. The normothermic perfusion mode will be discussed first followed by
a discussion of hypothermic perfusion mode. Repetitive description will
be omitted as much as possible.

[0161] In the normothermic or near-normothermic perfusion mode, an organ
is perfused for preferably 1/2 to 6 hours, more preferably 1/2 to 4
hours, most preferably 1/2 to 1 hour, with a medical fluid maintained
preferably within a range of approximately 10° C. to 38°
C., more preferably 12° C. to 35° C., most preferably
12° C. to 24° C. or 18° C. to 24° C. (for
example, room temperature 22-23° C.) by the thermoelectric unit
30a disposed in heat exchange communication with the medical fluid
reservoir 10.

[0162] As discussed above, in this mode, the medical fluid is preferably
an oxygenated cross-linked hemoglobin-based bicarbonate solution.
Cross-linked hemoglobin-based medical fluids can deliver up to 150 times
more oxygen to an organ per perfusate volume than, for example, a simple
University of Wisconsin (UW) gluconate type perfusate. This allows
normothermic perfusion for one to two hours to partially or totally
restore depleted ATP levels. However, the invention is not limited to
this preservation solution. Other preservation solutions, such as those
disclosed in U.S. Pat. Nos. 5,149,321, 5,234,405 and 5,395,314 and
co-pending U.S. patent application Ser. No. 08/484,601 and U.S. patent
application Ser. No. 09/628,311, filed Jul. 28, 2000, Attorney Docket No.
101311, the entire disclosures of which are hereby incorporated by
reference, may also be appropriate.

[0163] In the normothermic perfusion mode, the medical fluid is fed
directly to an organ disposed within the organ chamber 40 from one or the
other of bags 15a, 15b via tubing 50a,50b,50c or 50d,50e,50c,
respectively. The organ is perfused at flow rates preferably within a
range of approximately 3 to 5 ml/gram/min. Pressure sensor P1 relays the
perfusion pressure to the microprocessor 150, which varies the pressure
supplied by the pressure source 20 to control the perfusion pressure
and/or displays the pressure on the control and display areas 5a for
manual adjustment. The pressure is preferably controlled within a range
of approximately 10 to 100 mm Hg, preferably 50 to 90 mm Hg, by the
combination of the pressure source 20 and pressure cuff 15a, 15b in use
and the stepping motor/cam valve 65. The compressor and cuffs provide
gross pressure control. The stepping motor/cam valve 65 (or other
variable valve or pressure regulator), which is also controlled by the
operator, or by the microprocessor 150 in response to signals from the
pressure sensor P1, further reduces and fine tunes the pressure and/or
puts a pulse wave on the flow into the organ 60. If the perfusion
pressure exceeds a predetermined limit, the stepping motor/cam valve 65
may be activated to shut off fluid flow to the organ 60.

[0164] The specific pressures, flow rates and length of perfusion time at
the particular temperatures will vary depending on the particular organ
or organs being perfused. For example, hearts and kidneys are preferably
perfused at a pressure of approximately 10 to 100 mm Hg and a flow rate
of approximately 3 to 5 ml/gram/min. for up to approximately 2 to 4 hours
at normothermic temperatures to maintain and/or restore the viability of
the organ by restoring and/or maintaining pre-ischemia energy levels of
the organ, and are then preferably perfused at a pressure of
approximately 10 to 30 mm Hg and a flow rate of approximately 1 to 2
ml/gram/min. for as long as approximately 72 hours to 7 days at
hypothermic temperatures for storage and/or transport. However, these
criteria will vary depending on the condition of the particular organ,
the donor body and/or the donee body and/or on the size of the particular
organ. One of ordinary skill in the art can select appropriate conditions
without undue experimentation in view of the guidance set forth herein.

[0165] Effluent medical fluid collects in the bottom of the organ chamber
40 and is maintained within the stated temperature range by the second
thermoelectric unit 30b. The temperature sensor T2 relays the organ
temperature to the microprocessor 150, which controls the thermoelectric
unit 30a to adjust the temperature of the medical fluid and organ bath to
maintain the organ 60 at the desired temperature, and/or displays the
temperature on the control and display areas 5c for manual adjustment.

[0166] Collected effluent medical fluid is pumped out by the pump 80 via
tubing 81 through the filter unit 82 and then returned to the organ bath.
This filters out surgical and/or cellular debris from the effluent
medical fluid and then returns filtered medical fluid to act as the bath
for the organ 60. Once the level sensor L2 senses that a predetermined
level of effluent medical fluid is present in the organ chamber 40
(preferably enough to maintain the organ 60 immersed in effluent medical
fluid), additional effluent medical fluid is pumped out by the pump 90
through tubing 91. The temperature sensor T1 relays the temperature of
the organ bath to the microprocessor 150, which controls the
thermoelectric unit 30b to adjust the temperature of the medical fluid to
maintain the organ 60 at the desired temperature and/or displays the
temperature on the control and display area 5c for manual adjustment and
monitoring.

[0167] As noted above, the medical fluid can be directed to waste in a
single pass mode or recirculated eventually back to the organ and/or bath
(recirculation mode.)

[0168] Along tubing 91, the recirculated medical fluid is first pumped
through the filter unit 95. Use of a cross-linked hemoglobin medical
fluid allows the use of sub-micron filtration to remove large surgical
debris and cellular debris, as well as bacteria. This allows the use of
minimal antibiotic levels, aiding in preventing organ damage such as
renal damage.

[0169] Next, the recirculated medical fluid is pumped through the CO2
scrubber/O2 membrane 100. The medical fluid passes over the
hydrophobic macroporous membrane with a hydrophilic coating (for example,
Hypol) and a low vacuum is applied on the opposite side by activating
valve VV1 which removes CO2 from the recirculated medical
fluid.

[0170] Subsequently, a portion of the medical fluid then enters the
oxygenator 110 (for example, a JOSTRAT® oxygenator) and a portion is
diverted therearound passing via tubing 111 though the pH, pO2,
pCO2, LDH, T/GST and Tprotein sensor V1. At this point two gases,
preferably 100% oxygen and 95/5% oxygen/carbon dioxide, are respectively
placed on the opposite sides of the membrane depending on the pH level of
the diverted medical fluid. The gases are applied at a pressure of up to
200 mm Hg, preferably 50 to 100 mm Hg, preferably through a micrometer
gas valve GV3. The cross-linked hemoglobin-based bicarbonate medical
fluid may be formulated to require a pCO2 of approximately 40 mm Hg
to be at the mid point (7.35) of a preferred pH range of 7.25-7.45.

[0171] If the medical fluid exiting the oxygenator is within the preferred
pH range (e.g., 7.25-7.45), 100% oxygen is delivered to the gas exchange
chamber, and valve LV1 is then not opened, allowing the perfusate to
return to the reservoir 10 into the bag 15a or 15b not in use. If the
returning perfusate pH is outside the range on the acidic side (e.g.,
less than 7.25), 100% oxygen is delivered to the gas exchange chamber and
valve LV1 is then opened allowing the perfusate to return to the
organ chamber 40. Actuation of syringe pump 131 pumps, for example, one
cc of a bicarbonate solution from the bicarbonate reservoir 130, via
tubing 132 into the organ bath. Medical fluids with high hemoglobin
content provide significant buffering capacity. The addition of
bicarbonate aids in buffering capacity and providing a reversible pH
control mechanism.

[0172] If the returning perfusate pH is outside the range on the basic
side (e.g., greater than 7.25), 95/5% oxygen/carbon dioxide is delivered
to the gas exchange chamber and valve LV1 is not actuated, allowing
the perfusate to return to the bag 15a or 15b not in use. The bag 15a or
15b not in use is allowed to degas (e.g., any excess oxygen) through
valve GV4. When the bag 15a or 15b in use has approximately 250 ml
or less of medical fluid remaining therein, its respective cuff 16a, 16b
is allowed to vent via its respective gas valve GV1, GV2. Then,
the respective cuff 16a, 16b of the bag 15a or 15b previously not in use
is supplied with gas from the compressed gas source 20 to deliver medical
fluid to the organ to continue perfusion of the organ.

[0173] In the hypothermic mode, an organ is perfused with a cooled medical
fluid, preferably at a temperature within a range of approximately
1° C. to 15° C., more preferably 4° C. to 10°
C., most preferably around 10° C. The medical fluid is preferably
a crystalloid perfusate without oxygenation and preferably supplemented
with antioxidants and other tissue protecting agents, such as, for
example, ascorbic acid, glutathione, water soluble vitamin E, catalase,
or superoxide dismutase.

[0174] Instead of feeding the medical fluid directly to the organ, the
medical fluid may be fed from the reservoir tank 17 via tubing 51 into an
intermediary tank 70 preferably having a pressure head of approximately 5
to 40 mm Hg, more preferably 10 to 30 mm Hg, most preferably around 20 mm
Hg. Medical fluid is then fed by gravity or, preferably, pressure, from
the intermediary tank 70 to the organ 60 along tubing 50c by activating a
valve LV6. The level sensor 71 in the intermediary tank 70 is used
to control the feed from reservoir tank 17 to maintain the desired
pressure head. Because the medical fluid is fed to the organ by gravity
or, preferably, pressure, in the hypothermic mode, there is less
perfusion pressure induced damage to the delicate microvasculature of the
organ. In fact, the pressure at which the organ is perfused is limited by
the pressure head to at most 40 mm Hg.

[0175] The stepping motor/cam valve 205 (or other variable valve or
pressure regulator) may be arranged on the tubing 50c to provide
pulsatile delivery of the medical fluid to the organ 60, to decrease the
pressure of the medical fluid fed into the organ 60 for control purposes,
or to stop flow of medical fluid into the organ 60, as described above.

[0176] Further, in the hypothermic mode, because the organ 60 has less of
a demand for nutrients, the medical fluid may be provided to the organ 60
intermittently (e.g., every two hours at a flow rate of up to
approximately 100 ml/min.), or at a slow continuous flow rate (e.g., up
to approximately 100 ml/min.) over a long period of time. Intermittent
perfusion can be implemented in the single pass mode or recirculation
mode. The pump 80, filter unit 82 and tube 81 may be used to filter the
organ bath along with use of the pH, pO2, pCO2, LDH, T/GST and
Tprotein sensor; however, because the organ is unable to utilize oxygen
at hypothermic temperatures, the oxygenator is not used. If desired
and/or necessary, adequate oxygen can be obtained from filtered room air
or other suitable source.

[0177] Both the perfusate flow and the temperature regulation can be
automatically controlled. Such automatic control allows a rapid and
reliable response to perfusion conditions during operation. Automatic
flow control can be based on the parameters measured from the system,
including the perfusate flow rate, the perfusate pH exiting the organ,
the organ inlet pressure or timed sequences such as pre-selected flow
rates or switching between perfusate modes. Preferably, the flow control
is based on pressure monitoring of the perfusate inflow into the organ.
The benefits of automatic flow control include maintaining proper
oxygenation and pH control while operating under continuous flow or
controlled intermittent flow. Thermal control of the thermoelectric
devices (TED) can regulate the temperature of the organ cassette or
container and the perfusate reservoir. The thermal control is based on
thermal measurements made for example by thermistor probes in the
perfusate solution or inside the organ or by sensors in the TED.

[0178] The automatic control is preferably effected by an interactive
control program using easily operated menu icons and displays. The
parameters may be prestored for selection by a user or programmed by the
user during operation of the system. The control program is preferably
implemented on a programmed general purpose computer. However, the
controller can also be implemented on a special purpose computer, a
programmed microprocessor or microcontroller and peripheral integrated
circuit elements, an ASIC or other integrated circuit, a digital signal
processor, a hardwired electronic or logic circuit such as a discrete
element circuit, a programmable logic device such as a PLD, PLA, FPGA or
PAL, or the like. In general, any device capable of implementing a finite
state machine that is in turn capable of implementing the control process
described herein may be used. The control program is preferably
implemented using a ROM. However, it may also be implemented using a
PROM, an EPROM, an EEPROM, an optical ROM disk, such as a CD-ROM or
DVD-ROM, and disk drive or the like. However, if desired, the control
program may be employed using static or dynamic RAM. It may also be
implemented using a floppy disk and disk drive, a writable optical disk
and disk drive, a hard drive, flash memory or the like.

[0179] In operation, as seen in FIG. 15, the basic steps of operation to
control perfusion of one or more organs include first inputting organ
data. The organ data includes at least the type of organ and the mass.
Then, the program will prompt the user to select one or more types of
perfusion modes. The types of perfusion modes, discussed above, include
hypothermic perfusion, normothermic perfusion, and sequential perfusion
using both normothermic and hypothermic perfusion. When both normothermic
and hypothermic perfusion are employed, the user can select between
medical fluids at different temperatures. Of course, the system includes
default values based on previously stored values appropriate for the
particular organ. The user may also select intermittent perfusion, single
pass perfusion, and recirculation perfusion. Depending on the type of
perfusion selected, aerobic or anaerobic medical fluids may be specified.

[0180] Next, the type of flow control for each selected perfusion mode is
set. The flow control selector selects flow control based on at least one
of perfusate flow rate, perfusate pH, organ inlet pressure and timed
sequences. In the preferred embodiment, the flow control is based on
detected pressure at the perfusion inlet to the organ. The flow of the
medical fluid is then based on the selected perfusion mode and flow
control.

[0181] During operation the conditions experienced by the system, in
particular by the organ and the perfusate, are detected and monitored.
The detected operating conditions are compared with prestored operating
conditions. A signal can then be generated indicative of organ viability
based on the comparison. The various detectors, sensors and monitoring
devices are described above, but include at least a pressure sensor, a pH
detector, an oxygen sensor and a flow meter.

[0182] The control system may also include a thermal controller for
controlling temperature of at least one of the perfusate and the organ.
The thermal controller can control the temperature of the medical fluid
reservoirs and the organ container by controlling the TEDs. As noted
above, temperature sensors are connected to the controller to facilitate
monitoring and control.

[0183] The control system may be manually adjusted at any time or set to
follow default settings. The system includes a logic circuit to prevent
the operator from setting parameters that would compromise the organ's
viability. As noted above, the system may also be operated in a manual
mode for sequential hypothermic and/or normothermic perfusion, as well as
in the computer controlled mode for sequential hypothermic and/or
normothermic perfusion.

[0184] The above described apparatus and method may be used for child or
small organs as well as for large or adult organs with modification as
needed of the cassettes and or of the pressures and flow rates
accordingly. As previously discussed, the organ cassette(s) can be
configured to the shapes and sizes of specific organs or organ sizes. The
apparatus and method can also be used to provide an artificial blood
supply to, such, for example, artificial placentas cell cultures, for
growing/cloning organ(s).

[0185] While the invention has been described in conjunction with specific
embodiments thereof, it is evident that many alternatives, modifications
and variations may be apparent to those skilled in the art. Accordingly,
the preferred embodiments of the invention as set forth herein are
intended to be illustrative, not limiting. Various changes may be made
without departing from the spirit and scope of the invention.